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ID PMID Title PublicationDate abstract
12838063 Outcome after single technique ankle arthrodesis in patients with rheumatoid arthritis. 2003 Jul The established treatment for severe rheumatoid arthritis in the ankle is arthrodesis. Numerous reports in the literature describe outcomes in patients with degenerative and posttraumatic arthrosis and rheumatoid disease. This has led to results that are difficult to interpret. In addition, in the few studies that have evaluated patients with rheumatoid disease many techniques of arthrodesis are reported, further confounding assessment of one fusion method. One technique of 20 ankle fusions in patients with rheumatoid disease was evaluated. A modified Wagner arthrodesis was used through a transfibular approach using parallel compression screws. The scoring systems of Mazur et al, Moran et al, and the Short-Form-36 were used to evaluate the outcome. The mean time to followup was 3 years 10 months. Eighteen of 20 fusions obtained a solid talocrural union (90%). No correlation was found between the scores of Mazur et al and Moran et al. Correlation was achieved between the scores for the Short Form-36 and Moran et al. The modified Wagner ankle arthrodesis is a simple, reliable, reproducible technique with a 90% union rate. The value of the technique has been confirmed in patients with rheumatoid arthritis by evaluating the outcome using a scoring system that is validated and relevant to this population.
12528103 Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. 2003 Jan OBJECTIVE: To evaluate trends in and risk factors for mortality among patients with rheumatoid arthritis (RA) over a 40-year period. METHODS: A population-based inception cohort was assembled from among all Rochester, Minnesota residents ages > or =18 years who were first diagnosed with RA (fulfilling the 1987 American College of Rheumatology criteria for RA) between January 1, 1955 and December 31, 1994. Patients were followed up longitudinally through their entire medical records (including all inpatient and outpatient care by any provider) until death or migration from the county. Survival was described using the Kaplan-Meier method. Observed and expected survival were compared using the log-rank test, and standardized mortality ratios (SMRs) with expected survival were based on the sex and age of the study population and death rates from the Minnesota life tables. Cox proportional hazards models were used to estimate the influence of extraarticular manifestations and comorbidities, controlling for age, sex, body mass index (BMI), smoking, and rheumatoid factor positivity. RESULTS: Survival in this RA cohort was significantly lower than that expected in the population (P < 0.001) over the entire time period. Patients with RA were at significantly higher risk of death, with an SMR of 1.27 (95% confidence interval 1.13-1.41). Excess mortality among women was more pronounced than among men, with SMRs of 1.41 and 1.08, respectively. Presence of > or =1 extraarticular manifestation was the strongest predictor of mortality after adjusting for age, sex, BMI, smoking, and rheumatoid factor positivity. CONCLUSION: Survival in RA patients is significantly lower than expected. The strongest predictors of survival appear to be those related to RA disease complications, specifically, extraarticular manifestations of the disease and comorbidities. More attention should be paid to mortality as an outcome measure in RA.
14592482 Design and synthesis of orally active inhibitors of TNF synthesis as anti-rheumatoid arthr 2003 Nov 17 A novel series of TNF inhibitors was identified based on the screening of existing MMP inhibitor libraries. Further SAR optimization led to the discovery of a novel lead compound. Its synthesis, efficacy in experimental animal models, and pharmacokinetic data are discussed.
11960595 Chemokines as novel therapeutic targets in inflammatory diseases. 2002 Apr 1 Chemokines and their receptors are a large family of inflammatory molecules responsible for a number of biological functions, including the accumulation of leukocytes at tissue sites. Over the past 10 years, a number of studies have indicated a role for chemokines and chemokine receptors in the pathophysiology of several inflammatory diseases, examples of which are multiple sclerosis, atherosclerosis, rheumatoid arthritis, and gastrointestinal diseases including hepatic disease. For this reason, it is not surprising that modulation of their pharmacology could be a prime target for drug discovery. This commentary provides a brief synopsis of our current knowledge of the role of chemokines and their receptors in the inflammatory process, and highlights the pros and possibly cons of chemokine and chemokine receptor antagonism in the therapeutic approach to several inflammatory diseases.
14646817 [Transarticular atlanto-axial screw fixation for treatment of C1-C2 instability]. 2003 Nov Posterior transarticular screw fixation of the C1-C2 complex has become an accepted method of arthrodesis for patients requiring posterior C1-C2 fusion. Since 2000, four patients (2 males and 2 females) were treated with this surgical approach for management of atlantoaxial instability, including odontoid fracture with unilateral C1-C2 luxation, odontoid pseudarthrosis, complex congenital malformation of the craniovertebral junction and rheumatoid arthritis. All patients underwent stabilization with 2 transarticular C1-C2 screws, without any posterior interspinous graft. Patients were maintained in a rigid cervical orthesis 3 months postoperatively. Results were good, without any complication, after a short mean follow-up (8 months). Technical aspects of the technique are reported, The risk of screw malpositioning and vertebral artery or neural injury is minimal and can be lowered by using preoperative CT scan and MRI, and by using intraoperative fluoroscopy. Transarticular C1-C2 screw fixation proves to be a major surgical approach for treatment of atlantoaxial instability.
12105209 Signal transduction pathways involved in rheumatoid arthritis synovial fibroblast interleu 2002 Sep 20 Vascular cell adhesion molecule (VCAM)-1 has been implicated in interactions between leukocytes and connective tissue, including rheumatoid arthritis (RA) synovial tissue fibroblasts. Such interactions within the synovium contribute to RA inflammation. Using phosphoinositide 3-kinase (PI3-kinase) inhibitor LY294002 and Src inhibitor PP2, we show that interleukin (IL)-18-induced ERK1/2 activation is Src kinase-dependent. Antisense (AS) c-Src oligonucleotide (ODN) treatment reduced IL-18-induced ERK1/2 expression by 32% compared with control, suggesting an upstream role of Src in ERK1/2 activation. AS c-Src ODN treatment also inhibited Akt expression by 74% compared with sense control. PI3-kinase inhibitor LY294002 or AS PI3-kinase ODN inhibited Akt expression. AS c-Src ODN inhibited Akt phosphorylation, confirming Src is upstream of PI3-kinase in IL-18-induced RA synovial fibroblast signaling. IL-18 induced a time-dependent activation of c-Src, Ras, and Raf-1, suggesting this signaling cascade plays a role in ERK activation. IL-18 directly activated Src kinase by more than 4-fold over basal levels by enzymatic assay. Electrophoretic mobility shift assay showed that activator protein-1 (AP-1) is activated by IL-18 through ERK and Src but not through PI3-kinase. In an alternate pathway, inhibition of IL-1 receptor-associated kinase-1 (IRAK) with AS ODN to IRAK reduced IL-18-induced expression of nuclear factor kappaB (NFkappaB). Finally, IL-18-induced cell surface VCAM-1 expression was inhibited by treatment with AS ODNs to c-Src, IRAK, PI3-kinase, and ERK1/2 by 57, 43, 41, and 32% compared with control sense ODN treatment, respectively. These data support a role for IL-18 activation of three distinct pathways during RA synovial fibroblast stimulation: two Src-dependent pathways and the IRAK/NFkappaB pathway. Targeting VCAM-1 signaling mechanisms may represent therapeutic approaches to inflammatory and angiogenic diseases characterized by adhesion molecule up-regulation.
14667564 Evaluating changes in health status: sensitivity to change of the modified Arabic Health A 2003 Dec OBJECTIVE: To test the correlation between clinical improvements in patients with rheumatoid arthritis (RA) as defined by the American College of Rheumatology (ACR) response criteria and functional improvements as assessed by functional measures in the modified Arabic version of the Health Assessment Questionnaire (Arabic-HAQ) and to estimate the sensitivity to change of the Arabic-HAQ, in a prospective study. METHODS: Eighty-two patients with active RA were given methotrexate and followed up prospectively for 12 months. ACR response rates and score improvements on the modified Arabic-HAQ were compared. RESULTS: The Arabic-HAQ scores showed significant sensitivity to change after 6 and 12 months and were significantly correlated with the ACR response. Percentages of agreement with ACR response levels were high after 6 months and higher still after 12 months. Standardized effect sizes were 2.34 and 2.84 after 6 and 12 months, respectively. Relative efficiency of the total Arabic-HAQ score in relation to the tender joint count was greater than 1. CONCLUSION: The Arabic-HAQ is valid and sensitive to functional status changes in patients with RA. The results are comparable to those of the original HAQ. Thus, the Arabic-HAQ can be used to evaluate treatments and to identify changes that are important to RA patients.
14606345 Use and misuse of corticosteroids. 2003 Summer Corticosteroids are amongst the most common drugs used in clinical medicine. Prudent management of patients is essential to avoid steroid-induced complications.
15020330 Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes 2004 Apr BACKGROUND: Antibodies directed to proteins containing the non-standard amino acid citrulline, are extremely specific for rheumatoid arthritis (RA). Peptidylcitrulline can be generated by post-translational conversion of arginine residues. This process, citrullination, is catalysed by a group of calcium dependent peptidylarginine deiminase (PAD) enzymes. OBJECTIVE: To investigate the expression and activity of four isotypes of PAD in peripheral blood and synovial fluid cells of patients with RA. RESULTS: The data presented here show that citrullination of proteins by PAD enzymes is a process regulated at three levels: transcription-in peripheral blood PAD2 and PAD4 mRNAs are expressed predominantly in monocytes; PAD4 mRNA is not detectable in macrophages, translation-translation of PAD2 mRNA is subject to differentiation stage-specific regulation by its 3' UTR, and activation-the PAD proteins are only activated when sufficient Ca(2+) is available. Such high Ca(2+) concentrations are normally not present in living cells. In macrophages, which are abundant in the inflamed RA synovium, vimentin is specifically citrullinated after Ca(2+) influx. CONCLUSION: PAD2 and PAD4 are the most likely candidate PAD isotypes for the citrullination of synovial proteins in RA. Our results indicate that citrullinated vimentin is a candidate autoantigen in RA.
12687283 Case-control study of multiple myeloma with special reference to diet as risk factor. 2003 The case-control study was conducted in Belgrade (Yugoslavia) during the period 1994-1998. The objective of the study was to investigate factors related to the occurrence of multiple myeloma (MM). The study group consisted of 100 newly diagnosed MM patients and the same number of matched hospital controls. In the analysis conditional univariate and multivariate logistic regression were applied. According to multivariate analysis the following factors were significantly related to MM: smoking > or =25 cigarettes per day (Odds ratio--OR=6.7, 95% confidence interval--95% CI=1.3-34.3); having more than two brothers (OR=2.7, 95% CI=1.3-5.3), rheumatoid arthritis in personal history (OR=4.2, 95% CI=1.2-14.8), and frequent (4-7 times per week vs. lower frequency) consumption of yogurt (OR=3.1, 95% CI=1.6-6.0) and vegetables (OR=0.4, 95% CI=0.1-1.0).
11796874 Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. 2002 Jan A case of necrotising fasciitis in a patient receiving infliximab, an antitumour necrosis factor alpha (TNF-alpha) agent for rheumatoid arthritis, is presented. A widespread confluent, erythematous, pustular skin rash was the presenting sign. There was no fever throughout this admission. beta-Haemolytic group A streptococcus was isolated from blood cultures and skin swabs. The adductor muscles and fascia around the site of a previous hip arthroplasty were necrotic on exploration. The case highlights the risk of severe sepsis in patients on anti-TNF-alpha treatment.
12720045 Anemia, serum vitamin B12, and folic acid in patients with rheumatoid arthritis, psoriatic 2004 Jan OBJECTIVE: Although anemia is frequent in inflammatory rheumatic diseases, data regarding vitamin B12 status is scarce. The purpose of this study was to analyze the incidence and nature of B12 and folic acid (FA) deficiencies in a cohort of rheumatic patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and systemic lupus erythematosus (SLE). METHODS: Levels of B12, FA, and parameters of anemia were recovered or examined in 276 outpatients. In those with recent findings of low serum B12 levels, further studies of serum homocysteine (Hcy) and urine methylmalonic acid (MMA) levels were performed. RESULTS: The incidence of anemia was high: 49%, 46%, and 35%, in RA, SLE, and PsA, respectively. Low levels of serum B12 were also frequent (24%), with almost similar occurrence in the three disease groups. Deficiency in FA was rare (<5%). Mean levels of both vitamins did not differ significantly among the three groups. No correlation between serum B12 levels and anemia was found. In the 15 patients with recently detected low B12 levels, Hcy and MMA were evaluated before and following B12 therapy. In ten of them, baseline Hcy levels were high, while MMA was increased in one patient only. Response to B12 administration, i.e., a decrease in Hcy and/or MMA levels, was noticed in four patients only, suggesting that only 26% of the low-serum-B12 patients had true B12 deficiency. CONCLUSIONS: The incidences of anemia and decreased serum B12 levels were high in these three groups of rheumatic patients. However, true tissue deficiency seems to be much rarer.
12817094 Bringing the clinical experience with anakinra to the patient. 2003 May The recombinant interleukin-1 receptor antagonist, anakinra (Kineret; Amgen Inc., Thousand Oaks, CA), has been approved by the US Food and Drug Administration and the European Commission for the treatment of patients with active rheumatoid arthritis (RA). Approval was granted following the extensive evaluation of anakinra in five pivotal clinical trials that assessed its efficacy and safety in RA patients. These studies have indicated that anakinra has a favourable risk-benefit profile, producing rapid and sustained reductions in the signs and symptoms of RA, as measured by improvements in the American College of Rheumatology response criteria, particularly in patient-reported indicators of function and disability. The data from these trials suggest that anakinra is likely to provide a useful therapeutic option to clinicians and also meet the treatment expectations of patients with RA; however, further studies are underway to investigate additional benefits that anakinra may offer, particularly in patients with existing co-morbidities.
12817093 Addressing the safety of anakinra in patients with rheumatoid arthritis. 2003 May Anakinra (Kineret; Amgen Inc., Thousand Oaks, CA) is the first and only recombinant human interleukin-1 receptor antagonist available for therapeutic use. It has been approved by the US Food and Drug Administration and the European Commission for the treatment of patients with rheumatoid arthritis (RA). Anakinra, as an anti-rheumatic therapy, has been assessed in five placebo-controlled clinical trials, either alone or in combination with methotrexate. These trials have shown anakinra to be efficacious and well tolerated by most patients, with the most frequently reported adverse events being mild-to-moderate injection-site reactions that generally resolved rapidly. One of these trials was a large, prospective safety study, which included typical RA patients with a wide variety of co-morbid conditions and receiving concomitant medications. This confirmed that anakinra is a well-tolerated treatment in an RA population representative of that seen by the practising rheumatologist.
15022315 Haplotype analysis in simplex families and novel analytic approaches in a case-control coh 2004 Mar OBJECTIVE: Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a negative regulator of T cells and is, therefore, a strong candidate susceptibility gene for T cell-mediated autoimmune diseases. The association of CTLA-4 single-nucleotide polymorphisms (SNPs) with rheumatoid arthritis (RA) has been investigated previously, with inconsistent results. Recently, SNPs mapping to the gene (and not previously investigated in RA) have been associated with both type 1 diabetes mellitus and Graves' disease. The aim of this study was to investigate the association of the CTLA-4 polymorphism with RA. METHODS: Primer extension methods were used to genotype 5 haplotype-tagging SNPs (htSNPs) (-1722 T/C, -1661 A/G, -658 C/T, -319 C/T, and +49 A/G), and the TaqMan 5' allelic discrimination assay was used to genotype an additional 2 SNPs (CT60 and rs1863800) mapping to the CTLA-4 gene. Association to the 5 htSNPs was investigated using the transmission disequilibrium test in RA simplex families (n = 122). Allele frequencies for the htSNPs were also investigated in affected sibling pairs (n = 96) and unrelated controls (n = 173). For the SNPs CT60 and rs1863800, unrelated patients with RA (n = 759) were compared with controls (n = 755). RESULTS: No evidence for association to single markers or haplotypes of the 5 htSNPs was detected in either RA simplex families or the affected sibling-control cohort. Neither of the 2 SNPs recently associated with Graves' disease showed evidence for association in the unrelated patient-control cohort. CONCLUSION: No evidence for association of CTLA-4 with RA was detected using family or case-control methods.
12355137 Sonographic appearance of fibrous nodules in patellar clunk syndrome: a case report. 2002 Patellar clunk syndrome is a rare complication causing pain after total knee arthroplasty. However, it is important to differentiate it from the other causes of patellofemoral pain. In this article, we apply ultrasonography for the first time to demonstrate the suprapatellar fibrous tissue causing this condition. A 50-year-old woman with rheumatoid arthritis had left total knee arthroplasty. The patient had excellent results until 2 years after surgery, when she complained of anterior knee pain. On physical examination, a patellar "catch" and "pop" were noted from 45 degrees flexion to full extension. Roentgenograms showed a radiolucent line at the upper pole of the patella and no subluxation of the patella on skyline view. Sagittal and transverse gray-scale sonographic images revealed an echogenic area attached to the quadriceps tendon. Corresponding color Doppler sonographic images showed marked vascularity in this echogenic area. The patient was treated with removal of the suprapatellar tissue and a patellar component revision. Intraoperatively, the suprapatellar tissue, which measured 4 x 4 x 2 cm, entered the notch area of the femoral component on flexion and caused the patellar "pop" on knee extension. Pain relief was obtained immediately after the operation when smooth gliding motion of the patella was restored.
14747618 Expression of Fcgamma and complement receptors on peripheral blood monocytes in systemic l 2004 May OBJECTIVES: Fcagamma and complement receptors play an important role in the interaction between immune complexes (IC) and monocytes/macrophages. Recent work has demonstrated that their relative expression on these cells may be modified by cytokines, including TNF-alpha and IL-4. Furthermore, cytokines may alter the expression of adhesion molecules such as ICAM-1. However, little data exist on the in vivo expression of specific Fcgamma and complement receptors in systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), two diseases in which IC are important in pathogenesis. METHODS: Venous blood was obtained from 30 patients with SLE, 25 with RA and 25 healthy controls. Monocyte phenotype was determined by flow cytometric analysis of whole blood samples, with selective gating using forward and side scatter signals. Surface expression of Fcgamma receptors RI (CD64), RII (CD32) and RIII (CD16), complement receptors CR1 (CD35) and CR3 (CD11b/CD18), and adhesion molecules ICAM-1 (CD54) and CD11a (LFA-1) was determined. The effects of disease activity and corticosteroid therapy on the expression of these molecules were also examined. RESULTS: The expression of FcgammaRII was reduced on monocytes from patients with SLE compared with healthy controls and patients with RA (P = 0.002). This did not correlate with disease activity using conventional indices [SLEDAI (SLE disease activity index), C3/C4 levels and anti-double-stranded DNA antibody titres], and was independent of prednisolone therapy. There was no significant difference in FcgammaRI or RIII expression on SLE monocytes compared with healthy controls. In contrast, the expression of FcgammaRIII was increased on RA monocytes (P = 0.01), this being highest in patients with active disease. The proportion of FcgammaRIII-positive monocytes was also increased in RA, and prednisolone therapy was associated with a lower proportion of FcgammaRIII-positive cells. An increase in CR3 expression was seen on RA monocytes (P = 0.002), whilst CR1 was increased on monocytes from patients with active SLE or active RA. ICAM-1 expression was reduced on monocytes from patients with SLE (P = 0.002), although high-dose prednisolone therapy was associated with the lowest level of surface ICAM-1 on monocytes. CONCLUSIONS: Peripheral blood monocytes from patients with SLE or RA display significantly altered phenotypes compared with those from healthy controls. The observed reduction in SLE of FcgammaRII may represent a mechanism by which monocytes are protected from IC-mediated activation. Prednisolone therapy and disease activity had little effect on phagocytic receptor expression. The observed changes may reflect the different cytokine profiles seen in SLE and RA.
14528504 Intravenous human recombinant tumor necrosis factor receptor p55-Fc IgG1 fusion protein, R 2003 Oct OBJECTIVE: To determine the optimal dose regimen of intravenous (IV) Ro 45-2081 (lenercept), a tumor necrosis factor receptor p55-Fc IgG1 fusion protein, in patients with active rheumatoid arthritis (RA) METHODS: In a double-blind, placebo-controlled, parallel-group, multicenter trial, adult patients with long-standing active RA stabilized on conventional therapy were randomly assigned to receive 3 IV infusions, one every 4 weeks, of one of the following: (a) placebo, (b) lenercept 0.01 mg/kg (maximum 1 mg), (c) lenercept 0.05 mg/kg (maximum 5 mg), (d) lenercept 0.2 mg/kg (maximum 20 mg), or (e) lenercept 0.5 mg/kg (maximum 50 mg). The material utilized in the study had a lower relative bioavailability [lower area under the time-concentration curve (AUC) per mg infused] than that used in a recent similar trial. Efficacy variables included change from baseline in number of swollen joints and tender joints, scores on physician and patient assessments of disease activity, and patient assessment of pain. RESULTS: Patients treated with lenercept exhibited improvement as early as one day after the first IV infusion. The treatment benefit, however, was modest, maximized by 2 weeks and then diminished or vanished as non-neutralizing anti-lenercept antibody concentrations increased. The majority of adverse experiences were mild or moderate and not considered related to study drug. CONCLUSION: Our results showed that lenercept administered by IV infusion every 4 weeks is well tolerated, but only transiently effective in patients with long-standing RA, likely due to both the low relative bioavailability of the material used in the study and the formation of non-neutralizing anti-lenercept antibodies.
12429535 Purine enzymes in patients with rheumatoid arthritis treated with methotrexate. 2002 Dec OBJECTIVES: To study (a) purine metabolism during treatment with methotrexate (MTX) in patients with rheumatoid arthritis (RA) and (b) the relation of purine metabolism with efficacy and toxicity of MTX treatment. METHODS: One hundred and three patients with active RA who started treatment with MTX were included. The initial MTX dosage was 7.5 mg/week and raised to a maximum of 25 mg weekly if necessary. The purine enzymes 5'-nucleotidase (5'NT), purine-nucleoside-phosphorylase (PNP), hypoxanthine-guanine-phosphoribosyltransferase (HGPRT), and adenosine-deaminase (ADA) were measured before the start, after six weeks, and after 48 weeks or at study withdrawal. The laboratory results were related to measures of efficacy and toxicity of MTX treatment. RESULTS: Baseline values of 5'NT and PNP (16.9 and 206.8 nmol/10(6) mononuclear cells/h, respectively) were similar to those in former studies. Activities of HGPRT and ADA were relatively low at the start (8.7 and 80.3 nmol/10(6) mononuclear cells/h, respectively). After six weeks purine enzyme activities showed no important changes from baseline. After 48 weeks of MTX treatment a decrease of the enzyme activities of ADA (-21.6 nmol/10(6) mononuclear cells/h; 95% CI -28.6 to -14.7), PNP (-78.9 nmol/10(6) mononuclear cells/h; 95% CI -109.0 to -48.7), and HGPRT (-2.0 nmol/10(6) mononuclear cells/h; 95% CI -3.1 to -0.9) was found. No association was shown between the enzyme activities of ADA, PNP, and HGPRT, and the efficacy or toxicity of MTX treatment. In contrast, enzyme activity of 5'NT showed a decrease in the subgroup of patients discontinuing MTX treatment because of hepatotoxicity. CONCLUSION: MTX treatment in patients with RA leads to a significant decrease of the purine enzyme activities of ADA, PNP, and HGPRT that is not related to the anti-inflammatory efficacy or toxicity of MTX. Hepatotoxicity was related to a decrease in the enzyme activity of 5'NT. These changes may be explained by direct or indirect (via purine de novo and salvage metabolism and the homocysteine pathway) effects of MTX.
11855331 [Characteristics of salivary protein spectrum in patients with depressive disorders (in se 2002 Jan Salivary protein spectrum was studied by polyacrylamide gel electrophoresis in 80 patients with psychogenic affective disorders, 80 with rheumatic and 10 with reactive arthritis, and 9 patients with chronic renal insufficiency in the presence of depression. Control group consisted of 60 healthy subjects. The results indicate that depression is associated with decreased content of protein in different fractions of the spectrum, the most marked decrease being observed for the fraction with molecular weight of about 55 kD. The optical density of this fraction decreases to 0.11 units in depression (versus 0.17 +/- 0.02 in the control), which suggests that this method can be used for the diagnosis of depressions.