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ID PMID Title PublicationDate abstract
18270852 Diagnostic accuracy of immunoassays for the detection of antibodies to citrullinated prote 2008 Feb Anticitrullinated protein/peptide antibodies (ACPA) are highly specific for rheumatoid arthritis (RA). They can be found early in the disease course and are associated with more severe joint destruction and disease activity. In the last 4 years, important progress has been made in the detection and identification of ACPA, improving antigenic composition and epitope recognition. Consequently, many ACPA-ELISA kits have been developed by several manufacturers and are now commercially available. However, albeit their widespread use in clinical laboratories, the use of some kits has not been accompanied by a clinical validation nor by a comparative evaluation of their diagnostic accuracy. In addition, full automation of ACPA assays featuring ease of use, rapid response, and high productivity is just beginning to appear on the market and also deserves clinical and analytical validation. This review will consider the most relevant characteristics of the ACPA-ELISA assays and will describe the results of a comparative study performed with all the currently available second- and third-generation commercial methods.
18937651 Skin manifestations of rheumatoid arthritis: a study of 215 Turkish patients. 2008 Sep OBJECTIVE: To investigate the frequency and clinicopathological features of skin involvement in rheumatoid arthritis (RA), to find out whether early and aggressive disease-modifying treatment is changing the spectrum towards a milder disease pattern. METHODS: Two hundred and fifteen consecutive RA patients were enrolled. Main outcome measures were the frequency of cutaneous features and their relation to disease severity and treatment modality, ultrasound (USG) examination of nodules, histopathological examination of nodules and papules. RESULTS: Mean age and disease duration were 55.3 years and 138.1 months, respectively. Sixty-six percent of the patients had erosive disease, 70% were rheumatoid factor (RF) positive and 44% had Classes III and IV functional index. Among 43 patients having nodules, 20 were diagnosed as rheumatoid nodules (RNs) and the others as synovitis, bursitis, and so on, on clinical basis and by ultrasound. In 7 of 20 RNs, diagnosis was confirmed by histopathological examination. When clinical, histopathological, and USG data were analyzed collectively, sensitivity, and specificity of USG were found as 100 and 75%, respectively. Sixteen patients had relevant papular lesions. Fourteen of these were diagnosed as palisading neutrophilic granulomatous dermatitis (PNGD) and two as rheumatoid neutrophilic dermatitis (RND) on histopathological examination. Accelerated nodulosis was seen in one, and vasculitis in two of the patients. CONCLUSIONS: We observed a milder disease pattern compared to Anglo-Saxon countries with lower RN and vasculitis frequency. This cannot be explained by early and aggressive treatment as disease onset to treatment interval was long in our patient group. PNGD resembles RN in terms of frequency and association with severe disease.
18235966 Antibodies to citrullinated peptides are not associated with the rate of joint destruction 2008 Mar Antibodies to citrullinated peptides are highly specific for rheumatoid arthritis (RA) and represent a significant risk factor for undifferentiated polyarthritis. This prognostic ability may be related to the very diagnostic performance of these autoantibodies, since RA is a more erosive disease than other forms of arthritis. The present study evaluated an association of antibodies to citrullinated peptides and the rate of joint destruction in patients with a well-established diagnosis of RA. Seventy-one patients with RA were evaluated in 1994 and again in 2002 (functional class, joint count, Health Assessment Questionnaire score, hands X-ray). Autoantibodies (rheumatoid factor (RF), anti-perinuclear factor, anti-cyclic citrullinated peptide (CCP) antibodies) and Sharp's index were analyzed blindly. Delta Sharp was calculated as the difference in Sharp's index obtained in 1994 and 2002. During the follow-up the Health Assessment Questionnaire score increased from 0.91 +/- 0.74 to 1.39 +/- 0.72 (P < 0.001). Similarly, the number of swollen joints increased from 4.6 +/- 5.71 to 6.4 +/- 4.1 (P = 0.002). The frequency of autoantibodies and anti-CCP titer remained stable; however, serum RF concentration increased from 202.8 +/- 357.6 to 416.6 +/- 636.5 IU/mL (P = 0.003). Sharp's index increased from 56.7 +/- 62.1 to 92.4 +/- 80.9 (P < 0.001). No correlation was observed between Delta Sharp and the presence of RF, anti-perinuclear factor, and anti-CCP antibodies at baseline. Antibodies to citrullinated epitopes are specific and early markers for the diagnosis of RA but do not seem to be associated with the rate of joint destruction in patients with a well-established diagnosis of RA.
18358926 Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid a 2008 Mar 22 BACKGROUND: Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses. Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis. METHODS: In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratified by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10-25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20% improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria (ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00106548. FINDINGS: The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4.0 [95% CI 2.6-6.1], p<0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7-3.9], p<0.0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group. INTERPRETATION: Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis. FUNDING: F Hoffmann-La Roche, Chugai Pharmaceutical.
16447239 Reconstitution of peripheral blood B cells after depletion with rituximab in patients with 2006 Feb OBJECTIVE: To study the quantitative and phenotypic reconstitution of peripheral blood B cells and its relationship to the dynamics of clinical response in patients with rheumatoid arthritis (RA) following B cell depletion with rituximab. METHODS: Twenty-four patients with active RA treated with rituximab were studied. Flow cytometry with combinations of monoclonal antibodies to B cell and T cell subsets was used. RESULTS: The frequency and total number of CD19+ cells in the peripheral blood decreased a mean of 97% for more than 3 months in all but 1 patient following rituximab therapy. All B cell populations were depleted. More than 80% of residual B cells showed a memory or plasma cell precursor phenotype. B cell repopulation occurred a mean of 8 months after treatment and was dependent on the formation of naive B cells, which showed an increased expression of CD38 and CD5. During repopulation, increased numbers of circulating immature B cells, CD19+,IgD+,CD38(high),CD10(low),CD24(high) cells, were identified. Patients who experienced a relapse of RA on return of B cells tended to show repopulation with higher numbers of memory B cells. A small number of T cells and natural killer cells expressed low levels of CD20. These cells were depleted following rituximab therapy and returned to the circulation a mean of 5 months after treatment. No other significant changes were detected in the T cell populations studied. CONCLUSION: Rituximab induced a profound depletion of all peripheral blood B cell populations in patients with RA. Repopulation occurred mainly with naive mature and immature B cells. Patients whose RA relapsed on return of B cells tended to show repopulation with higher numbers of memory B cells.
18196443 Echocardiographic evaluation of cardiac diastolic function in patients with rheumatoid art 2008 May Rheumatoid arthritis (RA) is associated with increased cardiovascular mortality. However, cardiovascular findings are mostly subtle, and diastolic function abnormalities are one of the earliest manifestations. The aim of this study was to determine diastolic function abnormalities in RA patients and to make a reevaluation of diastolic function after 5 years of follow-up. Seventy-two RA patients (mean age: 48+/-11 years, F/M: 62/10) without any known cardiac disease and 67 controls (mean age: 46+/-11 years; F/M: 53/14) were recruited. Disease activity score (DAS), lipid values, and C-reactive protein (CRP) levels were determined. Left ventricular mass, isovolumetric relaxation time, mitral annular early (E), and late (A) diastolic filling rate were determined by M-mode two-dimensional color Doppler echocardiography. Mitral annular early (E') and late (A') diastolic velocities were also evaluated by tissue Doppler echocardiography. Twenty-four RA patients were reevaluated after 5 years of follow-up with DAS, biochemical variables, and echocardiography. Fifty five of 72 (76%) RA patients and 12 of the 67 (18%) controls had diastolic dysfunction (DD). Seven of ten patients with DD at baseline continued to have DD, whereas three did not show DD at 5 years. Six of 14 patients without DD at baseline developed DD at follow-up, while eight patients sustained normal diastolic function. Although DAS and lipid values were not altered during the course of 5 years, CRP levels decreased significantly (P<0.05). In conclusion, RA patients have diastolic function abnormalities compared to healthy controls. Five-year follow-up of a subgroup of our patients showed that, although clinical response was unsatisfactory, cardiac function was conserved without a major deterioration. Moreover, DMARDs, such as anti-TNFalpha agents, do not seem to have a major adverse effect on cardiac findings in these patients.
17849731 Back to the future: the managed care approach to rheumatoid arthritis. 2007 Jul Biologic disease-modifying antirheumatic drugs have been proven effective in the treatment of rheumatoid arthritis, but their efficacy literally comes at quite a high price to health plans. Therefore, MCOs are examining various strategies to provide coverage for these agents in a more cost-effective manner.
18687164 UK cost-utility analysis of rituximab in patients with rheumatoid arthritis that failed to 2008 Sep OBJECTIVE: To evaluate the incremental cost effectiveness of rituximab in patients with rheumatoid arthritis that failed to respond adequately to tumour necrosis factor-alpha inhibitors (biologic disease-modifying antirheumatic drugs; bDMARDs). A cost-utility model has been developed to simulate the long-term incremental cost and benefits of rituximab using data from clinical trials and registries. METHODS: The model estimates the lifetime disease progression of up to 10,000 hypothetical rheumatoid arthritis (RA) patients that failed one bDMARD. It compares cost and outcomes of two treatment sequences, representing the current UK standard both with and without rituximab. The population characteristics match those of the Randomised Evaluation of Long-term Efficacy of rituximab in RA (REFLEX) phase III randomised control trial. Clinical outcomes were based on an indirect comparison of published American College of Rheumatology response rates, adjusted for differences in placebo. To estimate medical resource use, health assessment questionnaire (HAQ) scores were grouped into five categories with UK registry data informing the average cost for each category. Quality-adjusted life years (QALYs) gained were mapped from disease severity (HAQ scores). RESULTS: Compared to a standard UK treatment sequence (assuming the sequential use of bDMARDs) the introduction of rituximab led to a QALY gain of 0.526 years. The incremental cost-effectiveness ratios (ICERs) based on total direct medical cost were 11,601 pounds. Adding rituximab to a treatment sequence with no sequential use of biologic generates an ICER of 14,690 pounds. CONCLUSION: Rituximab has lower average annual treatment costs compared to other bDMARDs and is a highly cost-effective treatment option for patients who have failed to respond adequately to one bDMARD. The cost per QALY gained of rituximab falls well below commonly accepted thresholds within the UK. Potential weaknesses of the model include the paucity of data on the efficacy of bDMARDs or non-biologic DMARDs when used as second-line options; the lack of consensus about the most appropriate therapy in patients who fail all available bDMARDs; probable underestimation of the non-drug related medical costs; indirect measurement of QALY gains with rituximab therapy; and the necessity of synthesising data from a number of clinical trials with different populations and study drugs.
16421679 Higher preoperative D-dimer value remain high postoperatively in patients with rheumatoid 2006 The differences in hemostatic condition between patients with inflammatory rheumatoid arthritis (RA) and noninflammatory osteoarthrosis (OA) were studied. Twenty-six patients undergoing total knee arthroplasty were enrolled. Compared with OA patients, RA patients showed a higher platelet count and D-dimer value preoperatively, and D-dimer remained high for 1 week after the operation. Patients with OA showed popular DD change, with the lowest value observed before the operation, and a gradual increase for 1 week after the operation. The highest value of thrombin-antithrombin complex was observed immediately after the operation. Fibrinogen and the clot rate at 1 week after operation were higher in both patient groups. We concluded that patients with RA showed different perioperative hemostatic change than patients with OA.
16711432 [Effects and mechanism of total saponins of Psammosilene tunicoids against rheumatoid arth 2006 Mar OBJECTIVE: To observe the antiarthritic effects and the possible mechanism of total saponins of Psammruosilene tunicoids (TSPT) against rheumatoid arthritis (RA). METHOD: After establishing AA rat model, the TSPT'S antiarthritic effects and mechanism against RA were studied through observing the changes of ankle swelling, arthritis index and levels of IL-1beta and TNF-alpha after medication. RESULT: TSPT could effectively inhibits articular swelling, decrease arthritis index and regulate down the content of IL-1beta and TNF-alpha in the inflammatory tissue soak of AA rats. CONCLUSION: TSPT has good antiarthritic effects and the possible mechanism may be related to its down-regulation of IL-1beta and TNF-alpha.
18490431 Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheu 2009 Jun OBJECTIVE: To validate and compare the definition of the Disease Activity Score 28 based on C-reactive protein (DAS28 (CRP)) to the definition based on erythrocyte sedimentation rate (ESR). METHODS: Data were analysed from two randomised, double-blind, placebo-controlled trials of abatacept of 6-month and 12-month duration in patients with rheumatoid arthritis. European League Against Rheumatism (EULAR) response criteria and the proportion of patients in remission (DAS28 <2.6) based on the two DAS28 definitions were examined. Trends in radiographic progression (erosion score, joint space narrowing score and total score) and physical function (Health Assessment Questionnaire Disability Index (HAQ-DI)) across the EULAR responder states (none, moderate and good) were analysed. RESULTS: There was general agreement in determining the EULAR responder state using both DAS28 definitions (kappa = 0.80, 95% CI 0.76 to 0.83). Overall, there was 82.4% agreement on the EULAR response criteria; when disagreements occurred, the DAS28 (CRP) yielded a better EULAR response more often then DAS28 (ESR) (12.6% vs 4.9%, respectively). There was also agreement in determining remission: kappa = 0.69 (95% CI 0.60 to 0.78). Radiographic progression decreased in patients treated with abatacept across EULAR states (from none to moderate to good) based on both definitions. For patients treated with placebo, the trend was not as pronounced, with radiographic scores higher for moderate vs non-responders. For physical function, similar trends were observed across the EULAR states for both DAS28 definitions. CONCLUSIONS: The DAS28 (CRP) has been validated against radiographic progression and physical function. While the DAS28 (CRP) yielded a better EULAR response more often than the DAS28 (ESR), the validation profile was similar to the DAS28 (ESR), indicating that both measures are useful for assessing disease activity in patients with rheumatoid arthritis.
18455686 Translating basic research into clinical rheumatology. 2008 Apr Findings from basic research in combination with precise clinical observations of the disease course in rheumatoid arthritis (RA) have led to the development of a multistage model to explain the pathophysiology of RA. Different cellular and soluble mediators, which play principal roles at different phases of the disease, have been identified. New therapeutic agents, which specifically target these factors, now allow us to intervene at several levels of the pathogenesis. This has already resulted in significant improvements for patients suffering from RA, and the development of new promising agents continues at a high pace. However, many questions concerning the optimal use of the new therapies remain unanswered. Combined efforts of basic research and clinical trials investigating the optimal timing and combination of the new treatments will be necessary to allow them to achieve their full potential and to result in the maximum benefit for patients.
17882223 Associations of killer cell immunoglobulin-like receptor genes with complications of rheum 2007 Dec We investigated whether killer cell immunoglobulin-like receptor (KIR) genes are risk factor(s) for rheumatoid arthritis (RA) and its clinical manifestations. One hundred and seventy-seven RA patients and 243 healthy individuals were tested for the presence of 11 KIR genes using PCR-SSP method. The frequencies of KIRs in patients with RA were similar to the frequencies in controls. However, RA patients positive for KIR2DL3 and negative for KIR2DS3 had earlier disease diagnosis. Additionally, KIR2DL2 and KIR2DS2 were significantly more frequent among RA patients with extra-articular manifestations and in its subgroup with vasculitis than in controls and in patients without these complications. Furthermore, the frequencies of KIR2DS1 and KIR3DS1 were lower in patients without bone erosions compared with healthy individuals. Relationships between the presence or absence of autoantibodies (rheumatoid factor and anti-cyclic citrullinated peptide) and KIR frequencies were also evaluated, but no significant differences were observed. These results suggest that particular clinical manifestations of RA may have different genetic backgrounds with respect to KIR genotype.
16924276 Atherogenic lipid profiles in rheumatoid arthritis. 2006 Aug 18 AIMS: Rheumatoid arthritis is associated with an excess mortality from cardiovascular disease, and this may be related to an atherogenic lipid profile. We set out to identify whether there was a correlation between disease activity and levels of different lipid fractions in a stable population of patients with rheumatoid arthritis on disease-modifying therapy. METHODS: Patients with rheumatoid arthritis were selected from our database and requested to have inflammatory markers and a fasting lipid profile taken at their next visit for monitoring of their disease modifying therapy. RESULTS: 204 patients were recruited for the study. A statistically significant relationship exists between reduced HDL and elevated CRP (p=0.01) and ESR (p=0.041). Elevated ESR, but not elevated CRP, was associated with raised LDL cholesterol (p=0.014). Fourteen patients (6.8%) were receiving statin therapy and 71 (34.8%) were taking prednisone. Use of prednisone, independent of dose, was associated with elevated triglyceride levels (p=0.041). CONCLUSIONS: This study supports previous work showing that rheumatoid arthritis is associated with an adverse lipid profile. While good disease control is clearly important, we should not neglect management of traditional cardiovascular risk factors.
16724862 An hypothesis to link the opposing immunological effects induced by the bacterial lysate O 2006 Extracts of lysed pathogenic bacteria were developed approximately 4 decades ago as oral vaccines in order to stimulate efficient specific immune and proinflammatory responses in patients experiencing recurrent infections, the ultimate aim being to rid the patient of the pathogen responsible for the infections. OM-89, a lysate of Escherichia coli, is clinically effective in patients who experience recurrent urinary tract infections by activating both innate and adaptive immunity. If immune activation is necessary to combat infectious pathogens, it may appear at first sight to be detrimental in patients with autoimmune diseases. However, OM-89 has also shown clear efficacy in patients with rheumatoid arthritis or with undifferentiated spondyloarthropathies, probably through oral tolerance and the long-term activation of regulatory cells. These phenomena may be explained by a hypothesis that immune exclusion and oral tolerance, both key functions of the gut, may be boosted by adjuvant-like molecules within orally administered OM-89.
17407238 A multireader reliability study comparing conventional high-field magnetic resonance imagi 2007 Apr The use of extremity low-field magnetic resonance imaging (E-MRI) is increasing, but relatively few data exist on its reproducibility and accuracy in comparison with high-field MRI, especially for multiple readers. The aim of this multireader exercise of rheumatoid arthritis wrist and metacarpophalangeal joints was to assess the intermachine (high vs low-field) agreement and to assess the interreader agreement on high and low-field images. Study findings suggested that E-MRI performs similarly to conventional high-field MRI regarding assessment of bone erosions. However, for synovitis and bone edema, considerable intermachine and interreader variability was found. Further studies are needed before recommendations on multireader E-MRI assessment of these pathologies can be given.
16447212 Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extra 2006 Feb OBJECTIVE: To investigate the incidence of noncardiac vascular disease in patients with rheumatoid arthritis (RA) and its relationship to systemic extraarticular disease in a community-based cohort. METHODS: A retrospective medical record review of 609 patients with incident RA diagnosed during 1955-1994 was carried out in Olmsted County, Minnesota. Patients were followed up from 1955 to 2000 (median followup 11.8 years). Incident noncardiac vascular disease and severe extraarticular RA manifestations (including pericarditis, pleuritis, and vasculitis) were recorded according to predefined criteria, and incidence rates were estimated. Using Cox proportional hazards models, the risk (hazard ratio [HR]) of developing vascular events was assessed in patients with and without severe extraarticular RA. RESULTS: Cerebrovascular and peripheral arterial events occurred in 139 patients (22.8%). The 30-year cumulative incidence rates of peripheral arterial events, cerebrovascular events, and venous thromboembolic events were estimated to be 19.6%, 21.6%, and 7.2%, respectively. The presence of severe extraarticular RA manifestations was found to be associated with all subgroups of noncardiac vascular disease except cerebrovascular disease alone (HR 2.3, 95% confidence interval [95% CI] 1.2-4.3 for peripheral arterial events; HR 3.7, 95% CI 1.3-10.3 for venous thromboembolic events; HR 1.5, 95% CI 0.7-3.2 for cerebrovascular events) after adjusting for age, sex, body mass index, smoking, and rheumatoid factor status. CONCLUSION: This is the first study to assess the incidence of noncardiac vascular disease in RA. Severe extraarticular RA was associated with all forms of noncardiac vascular disease except cerebrovascular disease alone. Similar to cardiac disease, the excess risk of noncardiac vascular disease in RA is likely to be related, in part, to the systemic inflammation associated with the extraarticular manifestations of RA.
17849729 Current management of rheumatoid arthritis. 2007 Jul Rheumatoid arthritis (RA), the most common form of inflammatory arthritis, is a chronic, inflammatory, progressive disease. Most patients have moderate disease, with a variable disease course and symptomatic flares interspersed with periods of relatively lower disease activity. Over the last 2 decades, the treatment of RA has evolved dramatically, from use of disease-modifying antirheumatic drugs to newer biologics. None of these therapies represents a cure for RA; however, the availability and the efficacy of multiple treatments has made remission of the disease a realistic target.
16880575 Severe cutaneous adverse drug reaction to leflunomide: a report of five cases. 2006 Jul Medications used to treat human ailments are known to cause cutaneous reactions which may vary in their severity. Leflunomide, an immunomodulating agent recently introduced to treat rheumatoid arthritis, is reported to cause severe cutaneous reactions. We are reporting five such cases. All our patients were started on leflunomide for rheumatoid arthritis, 4-6 weeks before the onset of cutaneous reaction and were admitted to the hospital with the common complaints of fever, skin rash and generalized weakness. All of them had characteristic pattern of events such as delayed onset of reaction, widespread and long lasting skin rash and internal organ involvement. These features suggest a possibility of drug hypersensitivity syndrome to leflunomide. Careful dosing and periodic monitoring of patients treated with leflunomide for possible adverse drug reaction is recommended.
17626917 Treating rheumatoid arthritis. 2007 Jul 14 Antitumour necrosis factor can produce remission if started early