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ID PMID Title PublicationDate abstract
17726252 Microvascular periodontal alterations: A possible relationship between periodontitis and r 2007 BACKGROUND: Microvascular involvements represent one of the first steps in many autoimmune diseases such as rheumatoid arthritis (RA). The aim of this study was to investigate the differences in periodontal microcirculation between healthy subjects and patients suffering from RA. METHODS: Thirty healthy subjects and 30 patients suffering from RA were examined. The patients who showed conditions known to compromise microcirculation, such as diabetes, hypertension, pharmacological treatments, were not included in the group of healthy patients. All the patients were non-smokers. Periodontal capillaroscopy was used to investigate the characteristics of microcirculation. Visibility, course, tortuosity, as well as the possible presence of microhemorrhages, the average caliber of the capillary loops and the number of visible capillary loops per square millimeter were evaluated for each patient. RESULTS: Microcirculation architecture in the healthy and in the RA patients was characterized by a network of capillaries in polygonal mesh with parallel orientation as regards the surface. In patients suffering from RA, it was possible to observe a reduced caliber of capillaries, as well as a greater number and elongated capillaries. No significant differences relating to oral capillaroscopic pattern were detected between RA patients that were rheumatoid factor, ANA, RANA positive and RA patients that were rheumatoid factor, ANA, RANA negative. CONCLUSIONS: This study shows that capillary alterations in patients suffering from RA occur in periodontal microcirculation; such evidence could be extremely important, suggesting that microvascular periodontal alterations may play a crucial part in the complex activity associated with periodontal disease in AR patients.
19221634 Role of cannabinoid receptors in bone disorders: alternatives for treatment. 2008 Dec A number of recent preclinical studies have demonstrated the potential role of cannabinoids and their receptors in bone metabolism. Pharmacological and genetic modulation of cannabinoid receptors indicate that cannabinoid ligands may provide attractive and novel agents for the treatment of bone diseases. This article reviews the role of cannabinoid receptors in regulating bone mass, bone loss and bone cell function in health and disease. The article also provides support to the notion that cannabinoid receptor ligands show a great promise in the treatment of bone diseases associated with accelerated osteoclastic bone resorption including osteoporosis, rheumatoid arthritis and bone metastasis.
18359293 Hydroxyl radical damaged immunoglobulin G in patients with rheumatoid arthritis: biochemic 2008 Jun OBJECTIVES: The role of hydroxyl radical (OH) damaged Immunoglobulin G (IgG) in rheumatoid arthritis (RA) has been investigated. DESIGN AND METHODS: The study was hypothesized that oxidative by-products, like OH-damage IgG, help to initiate autoimmunity in RA. To test this hypothesis, IgG was modified by OH. Immunogenicity of native and modified IgG was probed by inducing polyclonal antibodies in rabbits. Autoantibodies from 77 RA sera were screened by direct binding and competition ELISA. RESULTS: The OH caused extensive damage to IgG. The OH-IgG was found to be highly immunogenic in rabbits as compare to native IgG. High degree of specific binding by 72.7% RA sera autoantibodies towards OH-IgG was observed, in comparison to its native analogue (p<0.05). CONCLUSION: The OH modification of IgG causes perturbations, resulting in the generation of neo-epitopes, and making it a potential immunogen. The IgG modified with the .OH may be one of the factors for the induction of circulating RA autoantibodies.
18668604 Use of nonbiologic disease-modifying antirheumatic drugs and risk of infection in patients 2008 Aug 15 OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased frequency of and mortality from infections, which may be related to host factors, RA itself, inflammation, or medication side effects. This study was undertaken to determine the effect of nonbiologic disease-modifying antirheumatic drugs (DMARDs) on infection risk in RA. METHODS: We performed a retrospective, longitudinal study of a population-based RA cohort in British Columbia, Canada, followed from January 1996 to March 2003 using administrative data. We evaluated mild infections (requiring a physician visit or antibiotics) and serious infections (requiring or complicating hospitalization). Adjusted risk of mild and serious infections associated with DMARD exposure was estimated using generalized estimating equation extension of multivariate Poisson regression models, after adjusting for baseline covariates (age, sex, RA duration, socioeconomic status) and time-dependent covariates (corticosteroids, comorbidity, prior infections). RESULTS: A total of 27,710 individuals with RA provided 162,710 person-years of followup. Of these, 25,608 (92%) had at least 1 mild infection and 4,941 (18%) had at least 1 serious infection. Use of DMARDs without corticosteroids was associated with a small decrease in mild infection risk of statistical significance but unclear clinical significance (adjusted rate ratio [RR] 0.90, 95% confidence interval [95% CI] 0.88-0.93 relative to no corticosteroid or DMARD use). Use of DMARDs without corticosteroids was not associated with increased serious infection risk (adjusted RR 0.92, 95% CI 0.85-1.0). Use of corticosteroids increased the risk of mild and serious infections. CONCLUSION: Our results indicate that use of nonbiologic DMARDs, including methotrexate, does not increase the risk of infection in RA, whereas use of corticosteroids does. This has important implications for counseling individuals with RA concerning risks and benefits of DMARDs.
16567019 Biologics in development for rheumatoid arthritis: relevance to osteoarthritis. 2006 May 20 The osteoarthritis disease process affects not only the cartilage but also the entire joint structure, including the synovium, bone and periarticular muscles. Characteristically, abnormal biomechanical forces result in an imbalance between chondrocyte anabolic and catabolic pathways, which ultimately leads to progressive joint destruction. Within cartilage and synovium, pro-inflammatory cytokines, particularly IL-1b and TNF-a, auto-catalytically stimulate their own production and induce chondrocytes to produce additional catabolic mediators, including proteases, chemokines, nitric oxide, and prostaglandins. The success of targeted biological therapy in rheumatoid arthritis has taught that the blockade of a single dominant cytokine can lead to remarkable clinical benefit, even in complex disease. The effectiveness of biologicals in inflammatory arthritides as disease modifying agents has increased the likelihood that similar strategies can be developed to target specific molecular mechanisms in osteoarthritis (OA). However, since the clinical development program for disease-modifying OA drugs (DMOADs) is complicated by the slow progression of disease in many patients, the introduction of DMOADs will be greatly enhanced by advances in imaging and biomarkers that serve as validated surrogate endpoints for meaningful clinical outcomes.
19032830 Serum soluble CD30 in early arthritis: a sign of inflammation but not a predictor of outco 2008 Sep OBJECTIVE: To evaluate serum soluble CD30 levels (sCD30) in an early arthritis series and assess their ability to predict the outcome in patients with rheumatoid arthritis (RA) and undifferentiated arthritis (UA) at one year follow-up. METHODS: Serum sCD30 levels were measured by ELISA from 92 adult patients with RA and UA at baseline and from 60 adult controls. The patients were followed up for one year in the Kuopio 2000 Arthritis Survey. Receiver operating characteristic (ROC) curves were constructed to determine cut off points of sCD30 in RA and UA that select the inflammatory disease from controls. Sensitivity, specificity and positive likelihood ratio, and their 95 % CIs were calculated for sCD30 levels in RA and UA. RESULTS: Median serum sCD30 levels were higher in RA 25.1 (IQ range 16.3-38.6) IU/ml (p<0.001) and in UA 23.4 (15.4-35.6) IU/ml (p<0.001) than in controls 15.1 (10.7-20.8) IU/ml. No differences were recorded between RA and UA (p=0.840). Serum sCD30 levels at baseline did not predict remission at one year follow-up. CONCLUSION: Serum sCD30 levels were higher in RA and UA than in controls at baseline but they did not predict remission at one year follow-up in this series.
19007577 [Expectations, preferences and satisfaction of patients with rheumatoid arthritis receivin 2008 Oct 18 BACKGROUND AND OBJECTIVE: Our goal was to assess expectations, preferences and treatment satisfaction in patients suffering from rheumatoid arthritis (RA) treated with infliximab and their relationship with health related quality of life in real clinical practice. PATIENTS AND METHOD: 198 patients with AR participated in the study who started medication with infliximab at the beginning of the survey. Evaluation of expectations, preferences, satisfaction, health related quality of life, clinic evolution of patients and safety were made 2, 6, and 14 weeks after, coinciding with infliximab transfusions. RESULTS: More than 85% of the patients preferred to be treated in the hospital. They valued positively to be in contact with other patients, nurses and doctors in order to speak about their illness. Between 70% and 80% of the patients were satisfied with the infliximab treatment. After 2 weeks patients had reduced tender joint count by 70% and swollen joint count by 75%. At the end of the 14th week, 56.6% of the patients matched criteria ACR20, 31.5% ACR50 and 11.3% ACR70. 33.8% of patients had adverse events. The results in the EuroQol-5D indicated that patients improved their punctuations getting closer to those of the general population. Functional capacity of 50% of the patients improved significantly after the first 2 weeks of treatment and after 14 weeks this percentage reached the 70%. CONCLUSIONS: The results demonstrate that patients preferred to be treated in the hospital rather than in their houses. Also, patients reported a high level of satisfaction with infliximab.
17876645 Associations between HLA-DRB1, RANK, RANKL, OPG, and IL-17 genotypes and disease severity 2007 Dec We examined associations between human leukocyte antigen DRB1 (HLA-DRB1) shared epitope (SE), receptor activator of nuclear factor-kappaB (RANK), RANK ligand (RANKL), osteoprotegerin (OPG), and interleukin 17 (IL-17) genotypes with age of disease onset and radiographic progression in Japanese patients with early rheumatoid arthritis (RA). HLA-DRB1 genotypes were evaluated in 123 patients with early RA (98 female, 25 male) within 1 year of symptom onset. In 72 patients, radiographic progression over a 2-year period was evaluated using Larsen's methods, and genotypes of three polymorphic sites in RANK, five sites in RANKL, two sites in OPG, and three sites in IL-17 were determined by direct polymerase chain reaction sequencing. Possession of an SE allele was significantly associated with earlier disease onset in females (median 46.9 vs 51.9 years in SE- patients; P = 0.04). Single nucleotide polymorphisms (SNPs) in RANKL (rs2277438, P = 0.028) and IL-17 (rs3804513, P = 0.049) were significantly associated with radiographic progression at 2 years. RANKL-G-, SE- patients (n = 12) had significantly less joint damage than did RANKL-G+, SE- patients (n = 11; P = 0.0038), RANKL-G-, SE+ patients (n = 21; P = 0.0018) and RANKL-G+, SE+ patients (n = 28; P = 0.0024). In Japanese RA patients, HLA-DRB1 SE alleles are associated with disease onset at an earlier age, as has been observed in Caucasian RA patients. In addition, SNPs in RANKL and IL-17 may be associated with radiographic progression in Japanese patients with early RA.
17265488 Therapeutic effect of urocortin on collagen-induced arthritis by down-regulation of inflam 2007 Feb OBJECTIVE: To investigate the potential therapeutic action of the immunomodulatory neuropeptide urocortin (UCN) in an experimental model of rheumatoid arthritis (RA). METHODS: After disease onset, DBA/1J mice with collagen-induced arthritis (CIA) were treated with UCN, and the incidence, severity (clinical score), and joint histopathology were evaluated. The inflammatory response was determined by measuring the levels of different mediators of inflammation (cytokines and chemokines) in the joints and sera. The Th1-mediated autoreactive response was evaluated by determining the proliferative response and cytokine profile of draining lymph node cells stimulated with the autoantigen and by assaying the content of serum autoantibodies. The number of regulatory CD4+,CD25+ T cells and their capacity to suppress self-reactive Th1 cells were determined in joints and lymph nodes. RESULTS: UCN treatment significantly reduced the incidence and severity of CIA, completely abrogating joint swelling and cartilage and bone destruction. The therapeutic effect of UCN was associated with a striking reduction of the 2 deleterious components of the disease: the Th1-driven autoimmune response and the inflammatory response. UCN also induced the generation and/or activation of efficient interleukin-10/transforming growth factor beta1-producing Treg cells in arthritis with the capacity to suppress the autoreactive response and to restore immune tolerance, thus playing a pivotal role in the therapeutic effect of UCN. CONCLUSION: Our findings provide a powerful rationale for assessing the efficacy of UCN as a novel multistep therapeutic approach to the treatment of RA in humans.
16263783 A simple extension to the Rheumatoid Arthritis Quality of Life Questionnaire (RAQol) to ex 2006 Jan OBJECTIVES: To find out if the RAQol, if extended by a qualifying question on the level of concern associated with each item, can function both as a group outcome measure and as a useful tool to identify the concerns of individual patients. METHODS: Thirty-seven rheumatoid arthritis (RA) patients completed the questionnaire before and after starting a biological therapy. One hundred and forty-five others receiving routine care completed it at baseline, weeks 12 and 13 with EuroQol VAS and questions on global arthritis impact and any other concerns. Reproducibility was assessed in all 59 participants whose condition remained stable between weeks 12 and 13. RESULTS: The RAQol score was highly reproducible (intraclass correlation coefficient 0.986, n=59), reflected global RA impact (P = 0.000, n=140), negatively correlated with EuroQol VAS (Spearman coefficient=-0.639, two-tailed significance=0.000, n=142), responsive to biological therapy (two-tailed P= 0.000) and to increased global RA impact over 12 weeks (two-tailed P=0.012, n=37), and had high internal consistency (Cronbach's alpha=0.94, n=143). The number of issues of great concern and their percentage contribution to the RAQol score were related to global arthritis impact (P=0.000 for both) and reduced by a biological therapy (two-tailed P=0.000 and 0.001 respectively). The mean kappa for consistency in identifying each item as a concern was 0.801 (range 0.633-0.921). CONCLUSIONS: Use of the 'extended' RAQol in clinical practice could provide a valid and sensitive score for monitoring group outcome and a comprehensive and consistent list of an individual's main issues of concern to assist assessment of needs in routine clinical practice.
16490752 Synovial vascular patterns and angiogenic factors expression in synovial tissue and serum 2006 Aug OBJECTIVE: To determine whether subgroups of rheumatoid arthritis (RA) patients classified according to their synovial vascular pattern have a different expression of angiogenic mediators or exhibit distinct clinical or biological characteristics. METHODS: Arthroscopies were performed in 27 patients with RA and synovial samples were obtained. Vascular morphology was classified in three patterns: straight (S), tortuous (T) and mixed (M). Immunostaining was performed with anti-vascular endothelial growth factor (anti-VEGF), anti-vascular endothelial growth factor receptor (VEGFR)-1, anti-VEGFR-2, anti-IL-8 and anti-TGF-beta, and measured by digital image analysis. Serum levels of VEGF, TGF-beta and IL-8, and clinical, radiographic and serological data were also analysed. RESULTS: Eleven (41%) patients had the S pattern, nine (33%) the M pattern and seven (26%) the T pattern. The S and M groups had a higher prevalence of rheumatoid factor positivity and erosive disease, and higher levels of markers of systemic inflammation compared with the T group. Synovial expression of VEGF was higher in the S and T groups compared with the M group, whereas TGF-beta was higher in the T compared with the S and M groups. Distinct synovial distribution of VEGF and TGF-beta between groups was also observed. CONCLUSIONS: This preliminary study suggests that RA patients with the S and M patterns share different clinical, biological and serological characteristics compared with those with the T pattern, which may constitute a group with less severe disease. Differences in the intensity and distribution of synovial expression of VEGF and TGF-beta observed between groups could have pathophysiological relevance. However, larger, prospective multicentre studies would be need to determine the clinical relevance of vascular patterns in RA.
16079169 Excess recurrent cardiac events in rheumatoid arthritis patients with acute coronary syndr 2006 Mar BACKGROUND: Cardiovascular mortality is increased in rheumatoid arthritis. Possible reasons include an increased incidence of ischaemic heart disease or worse outcome after acute coronary syndrome (ACS). OBJECTIVES: To assess the outcome of ACS in rheumatoid arthritis compared with case matched controls in the context of underlying cardiac risk factors, clinical presentation, and subsequent management. METHODS: 40 patients with rheumatoid arthritis and ACS identified from coronary care admission registers between 1990 and 2000 were case matched as closely as possible for age, sex, classical cardiovascular risk factors, type and severity of ACS, and admission date (+/-3 months) with 40 controls. A standardised proforma was used for detailed case note review. RESULTS: Age, sex, other cardiovascular risk factors, and type and severity of presenting ACS were not significantly different between cases and controls. Recurrent cardiac events were commoner in rheumatoid arthritis (23/40, 57.5%) than controls (12/40, 30%) (p = 0.013); there were 16/40 deaths in rheumatoid arthritis (40%) v 6/40 (15%) in controls (p = 0.012). Recurrent events occurred earlier in rheumatoid arthritis (log rank survival, p = 0.05). Presentation with chest pain occurred in all controls compared with 33/40 rheumatoid patients (82%) (p = 0.006); collapse occurred in one control (2.5%) v 7/40 rheumatoid patients (17.5%) (p = 0.025). Treatment during the ACS was not significantly different in the two groups. CONCLUSIONS: Recurrent ischaemic events and death occur more often after ACS in rheumatoid arthritis. Atypical presentation is commoner in rheumatoid arthritis. There is an urgent need to develop identification and intervention strategies for ACS specific to this high risk group.
17663942 [Hearing impairment in patients with rheumatoid arthritis]. 2007 Jun OBJECTIVE: To evaluate the characteristics of hearing loss (HL) in patients with rheumatoid arthritis (RA). MATERIAL AND METHOD: A comparative case-control study was performed with 194 patients and 107 healthy subjects. All of them were submitted to pure-tone audiometry and detection of inflammatory parameters and Western blot for anticochlear antibodies. RESULTS: HL was detected in 42.7 % of patients with RA (15.9 % in controls; P.001). This was sensorineural in 38.6 %. Three or more altered blood parameters appeared in 28.9 % of patients with RA (17.6 % in controls; P<.01). We observed positive Western blot in 12 % of patients with RA and HL and none among healthy controls. CONCLUSIONS: There is a predisposition to HL, mainly sensorineural, in RA. In view of this prevalence, audiologic reviews must be performed to try to determine if this disorder shows an immunomediated aspect so that a therapeutic alternative could modify the course of HL.
17139665 Application of explicit process of care measurement to rheumatoid arthritis: Moving from e 2006 Dec 15 OBJECTIVE: To construct quality measures with measurement validity and meaning for clinicians. METHODS: We conducted a prospective cohort study of rates of change in disease-modifying antirheumatic drug (DMARD) and/or systemic corticosteroid drug or dose for 568 patients with rheumatoid arthritis (RA) across 6,159 clinical encounters within 12 months to examine how changes in clinical specifications change adherence. RESULTS: Rates of DMARD change were sensitive to specifications regarding the intensity of disease activity (severe or moderate), duration of specified disease activity, and length of the observation period. Over 12 months, the proportions of 377 patients with severe disease activity observed for 1-month, 2-month, and 3-month time blocks who had a change in DMARD drug or dose were 36%, 57%, and 74%, respectively. Over 12 months, a change in DMARD drug or dose was observed for 44%, 50%, and 68% of 377 patients with severe disease within 3 months, 6 months, and 12 months, respectively, of the patient meeting criteria for severe disease activity. A change in DMARD drug or dose was observed for 21%, 23%, and 34% of 149 patients with moderate disease activity within 3, 6, and 12 months, respectively, of the patient meeting criteria for moderate disease activity. CONCLUSION: Rates of pharmacologic interventions for patients with moderate and severe RA disease activity vary substantially by intensity and duration of disease activity and by duration of period for observing change. Lack of precision in explicit process criteria could substantially mislead comparisons of quality of care across comparison groups.
17336121 Cerebral vasculitis in a patient with rheumatoid arthritis. 2007 Mar Inflammatory vasculitis of the central nervous system is exceedingly rare in patients with rheumatoid arthritis (RA). The symptoms may be misleading. Most of the reported cases occurred in males with long-standing, nodular, destructive, rheumatoid factor-positive disease. Severe constitutional symptoms and prominent extraarticular manifestations of vasculitis were usually present. We report a case of cerebral vasculitis in a 59-year-old woman with a 20-year history of destructive rheumatoid factor-positive RA that was well controlled by methotrexate. Headache that was unresponsive to symptomatic treatment developed abruptly, together with gait disorders. Magnetic resonance imaging of the brain showed dot-like areas of high-signal in a periventricular subcortical distribution on both sides. Magnetic resonance angiography visualized a long tight stenosis of the right internal carotid artery and a string-of-beads stenosis of the left internal carotid artery suggesting vasculitis. Pulse therapy with methylprednisolone (1 g/d for 3 days) and cyclophosphamide (1 g) once a month ensured resolution of the neurological symptoms and laboratory evidence of inflammation. There was no evidence of a relapse at last follow-up after 5 months. Cerebral vasculitis is usually treated with monthly glucocorticoid and cyclophosphamide boluses separated by continuous glucocorticoid therapy. TNFalpha antagonists may be effective in patients who fail to respond to conventional treatment. However, other vasculitides such as giant cell arteritis and Wegener's granulomatosis must be ruled out, as they are refractory to TNFalpha antagonist therapy.
16783070 [Osteoporosis during rheumatoid arthritis and the peculiarities of its treatment]. 2006 May The goal of the work was to study the markers of bone metabolism and the indicators of mineral density of bone tissue (MDBT) in the patients with rheumatoid arthritis (RA). 40 patients with rheumatoid arthritis have been investigated who had not received the glucocorticosteroids. For investigation a complex of biochemical markers of bone metabolism have been applied. The obtained results have revealed the increase of excretion of calcium with urine which testifies the increased resorbtion of bone tissue in comparison to norm. The results of dual energy X-ray absorbtiometry (DEXA) have proved the frequency of osteopenia and osteoporosis during the RA; At the same time the inhomogenity of these indices in various fragments of the skeleton was shown. It has been established that lower indices of MDBT were revealed in patients with RA in proximal parts of hip bone and in distal part of forearm. Degree of osteopenia and osteoporosis in these fragments are in correlation with the indices of activity of inflammatory process which gives a possibility to recommend them as the indicators of generalization of osteoporosis. Revealing of osteopenia and osteoporosis in a distal part of the forearm at the earlier stages of the disease does not exclude a possibility of applying the indicators of MDBT as the early diagnostic markers.
16572442 The safety of infliximab, combined with background treatments, among patients with rheumat 2006 Apr OBJECTIVE: To assess the risk of serious infections following 22 weeks of infliximab therapy, and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis (RA) with various comorbidities. METHODS: Patients with active RA despite receiving methotrexate (MTX) were randomly assigned to receive infusions of placebo (group 1, n=363), 3 mg/kg infliximab (group 2, n=360), or 10 mg/kg infliximab (group 3, n=361) at weeks 0, 2, 6, and 14. At week 22, patients in placebo group 1 began receiving 3 mg/kg infliximab, and patients in group 3 continued to receive an infliximab dose of 10 mg/kg. Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg. RESULTS: At week 22, the relative risk of developing serious infections in groups 2 and 3, compared with group 1, was 1.0 (95% confidence interval [95% CI] 0.3-3.1, P=0.995) and 3.1 (95% CI 1.2-7.9, P=0.013), respectively. The incidence of serious adverse events was 7.8% in groups 2 and 3 compared with 7.5% in group 1. From week 22 to week 54, 11.8%, 9.9%, and 10.3% of patients in groups 1, 2, and 3, respectively, reported occurrences of serious adverse events. Through week 54, 1 patient in group 1, 2 patients in group 2, and 4 patients in group 3 developed active tuberculosis. CONCLUSION: The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone. Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22.
17012425 Single-stage revision of peri-prosthetic infection following total elbow replacement. 2006 Oct This study reviews the predisposing features, the clinical, and laboratory findings at the time of diagnosis and the results of single-stage revision of prosthetic replacement of the elbow for infection. Deep infection occurred in six of 305 (1.9%) primary total elbow replacements. The mean follow-up after revision was 6.8 years (6 months to 16 years) and the mean age at the time of revision was 62.7 years (56 to 74). All six cases with infection had rheumatoid arthritis and had received steroid therapy. The infective organism was Staphylococcus aureus. Four of the six elbows had a developed radiolucency around one component or the other. Successful single-stage exchange arthroplasty was carried out with antibiotic-loaded cement in five of the six cases. In one, the revision prosthesis had to be removed following recurrence of the infection. The functional result was good in three elbows, fair in one, poor in one and fair in the resection arthroplasty.
18240242 Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular di 2008 Feb OBJECTIVE: To examine the role of the variants of the PTPN22 and HLA-DRB1 genes as predictors of mortality in inflammatory polyarthritis (IP) and rheumatoid arthritis (RA). METHODS: Patients were recruited from a primary care-based inception cohort of patients with IP and were followed up prospectively. For patients who died, the cause and date of death was obtained. Cox proportional hazards regression models were used to assess the association of the HLA-DRB1 (including the shared epitope [SE]) and PTPN22 genes with the risk of death from all causes and from cardiovascular disease (CVD) and to assess the interactions between SE, smoking, and anti-cyclic citrullinated peptide (anti-CCP) status, adjusted by age at symptom onset and sex. RESULTS: DNA samples were available from 1,022 IP patients. During followup, 751 of them (74%) satisfied the American College of Rheumatology 1987 criteria for RA, and 242 of them (24%) died. Carriage of 2 copies of SE alleles predicted death from all causes (hazard ratio [HR] 1.57 [95% confidence interval (95% CI) 1.1-2.2]) and from CVD (HR 1.68 [95% CI 1.1-2.7]). This effect was most marked for individuals with the HLA-DRB1*01/*04 combination. An interaction of smoking, SE alleles, and anti-CCP antibodies was observed and was associated with the greatest risk of death from CVD (HR 7.81 [95% CI 2.6-23.2]). No association of the PTPN22 gene with mortality was detected. CONCLUSION: SE alleles, particularly compound heterozygotes, are associated with death from all causes and from CVD, independently of autoantibody status. However, the combination of SE, smoking, and anti-CCP antibodies is associated with a high risk of premature death in patients with IP and RA, which raises the possibility of a targeted strategy to prevent CVD in these patients.
16542506 Decrease in expression of bone morphogenetic proteins 4 and 5 in synovial tissue of patien 2006 Bone morphogenetic proteins (BMPs) have been identified as important morphogens with pleiotropic functions in regulating the development, homeostasis and repair of various tissues. The aim of this study was to characterize the expression of BMPs in synovial tissues under normal and arthritic conditions. Synovial tissue from normal donors (ND) and from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) were analyzed for BMP expression by using microarray hybridization. Differential expression of BMP-4 and BMP-5 was validated by semiquantitative RT-PCR, in situ hybridization and immunohistochemistry. Activity of arthritis was determined by routine parameters for systemic inflammation, by histological scoring of synovitis and by semiquantitative RT-PCR of IL-1beta, TNF-alpha, stromelysin and collagenase I in synovial tissue. Expression of BMP-4 and BMP-5 mRNA was found to be significantly decreased in synovial tissue of patients with RA in comparison with ND by microarray analysis (p < 0.0083 and p < 0.0091). Validation by PCR confirmed these data in RA (p < 0.002) and also revealed a significant decrease in BMP-4 and BMP-5 expression in OA compared with ND (p < 0.015). Furthermore, histomorphological distribution of both morphogens as determined by in situ hybridization and immunohistochemistry showed a dominance in the lining layer of normal tissues, whereas chronically inflamed tissue from patients with RA revealed BMP expression mainly scattered across deeper layers. In OA, these changes were less pronounced with variable distribution of BMPs in the lining and sublining layer. BMP-4 and BMP-5 are expressed in normal synovial tissue and were found decreased in OA and RA. This may suggest a role of distinct BMPs in joint homeostasis that is disturbed in inflammatory and degenerative joint diseases. In comparison with previous reports, these data underline the complex impact of these factors on homeostasis and remodeling in joint physiology and pathology.