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

ID PMID Title PublicationDate abstract
9292814 Development of polyarthritis after insertion of silicone breast implants followed by remis 1997 Sep We describe 2 HLA-identical sisters who both received silicone breast implants and subsequently developed polyarticular arthritis and neurologic symptoms. In both patients, HLA typing revealed 3 alleles typically associated with rheumatic diseases: HLA-DRB1*0405 and HLA-DQB1*0302 (associated with RA), and HLA-DRB4*01 (associated with mixed connective tissue disease and autoimmune reactions in patients with silicone breast implants. After removal of the implants, rheumatic as well as neurologic symptoms improved dramatically in both patients. One patient achieved complete remission. The other patient, who initially had more progressive disease, retained mild residual symptoms, but had significant improvement in radiological erosions. We believe that our cases support the theories that silicone may act as a triggering factor in genetically susceptible individuals, and that silicone may represent an adjuvant for the development of autoimmune disease. We discuss the possibility that a manifested spectrum of symptoms after silicone exposure might be more specific for a patient's genetic background than unique for silicone.
10381041 Modeling the lifetime costs of rheumatoid arthritis. 1999 Jun OBJECTIVE: To develop an analytical approach for estimating the lifetime costs of rheumatoid arthritis (RA) using existing population based cross sectional data, and to use this estimate to describe the potential cost-effectiveness of bone marrow transplantation for RA. METHODS: Estimates of arthritis related costs (direct, indirect, and nonmedical) and mortality were obtained from previously assembled population based cohorts. A mathematical model was designed defining 25 hypothetical ratios (RA/NA) representing the proportionate excess cost of RA each year for the 25 years following a diagnosis of RA. Using age and sex-specific cost estimates, we then simulated a vector of 25 ratios 1000 times. Each age and sex-specific randomly generated variable was converted to an estimated dollar amount (in 1995 dollars US) of excess cost attributable to RA. All dollar amounts were discounted by 3% per year. Finally, each vector of 25 discounted dollar amounts was summed to yield an estimate of the total excess medical costs in 1995 dollars for the first 25 years of a person's lifetime following a diagnosis of RA. Because not every one of these hypothetical individuals would be expected to live all 25 years, we used the standardized mortality ratio for an individual with RA (from our inception cohort) and multiplied it by the age-specific 1990 mortality rates for Minnesota whites to estimate how many of the 1000 randomly generated hypothetical individuals could be expected to die during each of the 25 years. For these, the summation of estimated cost was truncated at the death year. This process yielded, for each age and sex, a sample of 1000 sums of 25 (or fewer) excess costs all in terms of 1995 dollars that correspond to the excess cost during the first 25 years after an RA diagnosis, adjusted for differential survival among patients with RA compared to nonarthritic controls. The distribution of these sums thus represented a distribution of the 1995 dollars that could be saved if RA could be "cured" soon after incidence. RESULTS: Our simulation analyses indicated that the median lifetime incremental costs of RA range roughly from ,$61,000 to $ 122,000. Incremental costs were higher for younger individuals compared to older individuals and were consistent over all percentiles and age groups. No systematic relationship between the incremental costs of females with RA compared to males was identified. CONCLUSION: These data suggest that interventions such as autologous bone marrow transplantation, which has recently been estimated to cost roughly $60,000, may be cost saving if they eliminate the downstream incremental costs of RA.
11665966 Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium 2001 Oct OBJECTIVE: To investigate the presence of citrullinated proteins in the synovial membrane of patients with rheumatoid arthritis (RA) and controls, and to analyze a possible relationship with antifilaggrin autoantibody (AFA) reactivity. METHODS: Synovial biopsy samples were obtained from 88 consecutive patients undergoing needle arthroscopy for knee synovitis associated with RA (n = 36), spondylarthropathy (n = 35), osteoarthritis (n = 9), or other diagnoses (n = 8). Tissue sections were stained with 2 different anticitrulline polyclonal antibodies and an antifilaggrin monoclonal antibody (mAb). The phenotype of citrulline-positive cells and the colocalization with affinity-purified AFA were investigated by double immunofluorescence on frozen sections. RESULTS: Studies with the first antibody showed that citrulline is expressed intracellularly in the lining and sublining layers of RA synovial tissue. Staining with the second antibody, monospecific for proteins containing modified citrulline, and with anti-inducible nitric oxide synthetase confirmed the presence of citrullinated proteins rather than free citrulline in the synovium. Citrulline-positive cells were detected in 50% of the RA patients (18 of 36) but in none of the controls (0 of 52). The anticitrulline reactivity colocalized with affinity-purified AFA reactivity, although stainings with the antifilaggrin mAb indicated the absence of filaggrin in the synovium. CONCLUSION: Intracellular citrullinated proteins, which are not recognized by an antifilaggrin mAb, are expressed in RA but not in control synovium. The high specificity of this finding and the colocalization with AFA reactivity boost the interest in citrullinated proteins as possible triggers of autoimmune responses in RA. Moreover, this is the first description of a specific histologic marker for RA synovium.
10088764 Filtration leukocytapheresis therapy in rheumatoid arthritis: a randomized, double-blind, 1999 Mar OBJECTIVE: To determine the efficacy and safety of filtration leukocytapheresis (LCP) for the treatment of rheumatoid arthritis (RA). METHODS: Twenty-five patients with drug-resistant RA were randomly assigned to undergo filtration LCP and 7 to undergo sham apheresis (control group) in a randomized, double-blind, placebo-controlled study. Three apheresis procedures were performed, with 1-week intervals between procedures. The efficacy of filtration LCP was evaluated according to the American College of Rheumatology definition of improvement in RA. Medications for each patient were unchanged for at least 6 months prior to enrollment and throughout the study. RESULTS: Tender joint counts, swollen joint counts, patient assessment of pain and global severity, physician assessment of global severity, and Health Assessment Questionnaire Disability Index were significantly improved in the LCP group compared with the control group (P < 0.05 for patient assessment of pain; P < 0.01 for all others). Seventy-nine percent of the patients in the LCP group exhibited significant overall improvement, while none of the patients in the control group were improved (P < 0.001). CONCLUSION: The results indicate that filtration LCP is an effective and well-tolerated treatment for patients with drug-resistant RA.
9021280 Assessments of disability in women with rheumatoid arthritis in relation to grip force and 1997 Jan The aim of this study was to assess disability with the Health Assessment Questionnaire (HAQ) and to evaluate the relationships between grip force, pain and difficulty in daily activities. Twenty women with rheumatoid arthritis were assessed with measurements of grip force and pain before and after grip test. Both the original HAQ version and an alternative rating model, not taking the use of assistive devices into account, were used. All patients reported pain which significantly increased after grip test and with a significant inverse correlation to grip force. All patients had assistive devices, on average 15 devices (range 1-27). Ninety-one per cent of the patient's devices were in continued use, most frequently in the categories; Eating, Grip and Hygiene. Disability was significantly correlated to pain, grip force and use of assistive devices. When using the alternative ratings of 20 questions in HAQ, 8 of the 20 questions showed significantly (p = 0.0003-0.0339) lower scoring, and the number of questions with significant correlations between grip force and disability increasing from 9 (r = 0.48-0.74, p = 0.039-0.001) to 14 questions (r = 0.47-0.74, p = 0.047-0.001). Difference between intrinsic disability (without assistive devices) and actual disability (with such assistance) is not reflected in original HAQ. The present study indicates that assessment of actual disability by the alternative rating model is more often correlated to impairment (grip force) than disability assessed by original HAQ and can be considered to give a better assessment of actual disability than the original HAQ model.
11712757 The inhibition of metalloproteinases as a therapeutic target in rheumatoid arthritis and o 2001 Jun The collagenases of the matrix metalloproteinase family are key enzymes in mediating irreversible cartilage collagen loss in arthritis. Inhibition of these enzymes is, therefore, an important therapeutic target. New approaches to collagenase inhibition include active site inhibitors designed for specific enzymes, inhibition of cell signalling molecules and transcription factors involved in collagenase gene expression, prevention of zymogen activation and induction of natural inhibitor production.
9266133 The radiological assessment of rheumatoid arthritis. 1997 May Antirheumatic therapy has changed from a rather conservative approach towards more aggressive early intervention. Objective measures of the course and outcome of rheumatoid arthritis are essential to understand the disease process and evaluate the therapeutic response. Radiological evaluation fulfils many of the criteria of objectivity: the films provide a permanent record and can be evaluated serially and repeatedly; the changes do not fluctuate with disease activity; and good technique and correct timing can keep the radiation load to a very acceptable level. Consequently, therapies can be evaluated on the basis of their efficacy on radiological progression. In clinical practice, a visual qualitative assessment is usually sufficient, but for therapeutic trials or studies of disease progression in certain patient groups, quantitative methods are needed. A number of different evaluation systems have been introduced, but none of these have gained universal acceptance. No ideal evaluation method (which should be rapid, easy to use and have a good level of reproducibility) has yet been found. Here we make provisional recommendations on the conduct of future therapeutic trials to maximise the likelihood that they will give conclusive results using radiographic outcome assessments.
10225741 The mechanism of the efficiency of leukocytapheresis on rheumatoid arthritis. 1997 Aug This study was designed to determine the efficacy of filtration leukocytapheresis (LCAP) in the treatment of rheumatoid arthritis (RA) and the mechanism of its efficacy. Three filtration LCAP procedures in 22 RA patients were performed. Heparinized samples were collected from peripheral blood and synovial fluid. The surface markers of T cells were measured by flow cytometry before the first and third procedures. Proportions of activated and memory T cells in the peripheral blood were paradoxically higher after the third procedure than they were prior to the first treatment. Inversely, the activated T-cell counts in the synovial fluid decreased after the third procedure. In RA patients, higher proportions of activated T lymphocytes are present in RA affected joints than in the peripheral blood. If LCAP induced the redistribution of activated T cells from the affected joints into the circulating blood, the effectiveness of LCAP in the treatment of RA might be explained by the mechanism.
11346224 Total mortality is increased in rheumatoid arthritis. A 17-year prospective study. 2001 The purpose of this study was to determine the total and cause-specific mortality in rheumatoid arthritis (RA) patients compared to a control population in northern Norway. One hundred and eighty-seven patients with RA and 930 population controls matched for age, gender and municipality were followed until death or for a maximum of 17 years. The total mortality in RA patients was twice that of their controls (MRR = 2.0, 95% CI = 1.6-2.5). Patients possessing serum rheumatoid factors did not have a higher relative mortality than the seronegative patients. There was no statistically significant increased mortality from cancer or cardiovascular diseases. Indications for a higher death rate in RA patients than in controls were found for infection and sudden death.
10377916 Arthritis: new agents herald more effective symptom management. 1999 Jun For physicians and patients alike, managing the symptoms of rheumatoid and osteoarthritis is an ongoing challenge. Myriad therapies are available, although virtually all provide only temporary relief and produce side effects that interrupt long-term use. New disease-modifying antirheumatic drugs, biologic response modifiers, and cyclooxygenase inhibitors offer the promise of more effective, longer lasting symptom management and, in some cases, reduced side effects. The population of older persons affected by arthritis continues to grow. Increased familiarity with these new treatments will aid primary care physicians in helping older patients better manage their arthritis during the next decade.
9614552 Induction of apoptosis in the rheumatoid synovium by Fas ligand gene transfer. 1998 Mar We have recently reported that local administration of anti-Fas monoclonal antibody (MAb) in human T cell leukemia virus type 1 (HTLV-1) carrying mice improved arthritis due to the induction of apoptosis. This finding strongly indicated the beneficial therapeutic effect of Fas-mediated apoptosis in rheumatoid arthritis (RA). To establish further the therapeutic effect of Fas-mediated apoptosis on RA taking into consideration safety and practicality, we investigated the effect of cells transfected with human Fas ligand (hFasL) gene on proliferating human rheumatoid synovium engrafted in severe combined immunodeficiency (SCID-RA) mice. The hFasL transfectants exhibited cytotoxic activity against RA synoviocytes via the Fas/FasL system in vitro. Histopathological and immunohistochemical studies showed that local injection of irradiated-hFasL transfectants eliminated synoviocytes and mononuclear cells in engrafted human rheumatoid synovium of SCID-RA mice. Furthermore, in situ nick and labeling analysis confirmed that the cells in engrafted synovium frequently underwent apoptosis by irradiated-hFasL transfectants. Our results clearly demonstrated that hFasL transfectants induced apoptosis by cell-to-cell interaction via the Fas/FasL system. Thus, ex vivo gene transfer of FasL may represent a novel therapeutic strategy for RA.
12476781 Treatment of rheumatoid arthritis: new therapeutic approaches with biological agents. 2001 May Rheumatoid arthritis is a chronic polyarthritis leading to joint destruction and remarkable disability. Current therapies have various degrees of efficacy, but toxicity frequently limits their long-term use. Furthermore, treatment of refractory rheumatoid arthritis includes increasing disease-modifying antirheumatic drugs dosage, using combination therapy, and adding or increasing the posology of corticosteroids. Although the etiology of the disease remains unknown, our increasing knowledge of the mechanisms underlying pathogenic events in rheumatoid synovitis, has provided opportunities to specifically target cell surface markers or cytokines involved in the inflammatory response. The objective of this review is to describe the different therapeutic approaches with biological agents that are either being utilized or are under development. Some of these products reflect the evolving capacity for the biotechnology industry to synthesize and humanize therapeutic agents: anti-tumor necrosis factor (TNF) alpha monoclonal antibodies (MoAb) and recombinant TNF-receptor construct appear to be validated tools. These treatments alone, or in combination with methotrexate are very effective in rheumatoid patients. Data from clinical trials and issues related to mechanisms of action, potential toxicity, and future perspectives for these novel therapeutic options are considered in this review. Anti-cytokine treatment include other interesting approaches to interfere with on-going inflammatory processes, such as the use of recombinant human interleukin (IL)1 receptor antagonist, or recombinant human IL10. T cell constimulatory blockade, induction of apoptosis in the synovial tissue, and gene therapy could represent future strategies in rheumatoid disease.
9163666 Pneumocystis carinii pneumonia in a HIV-seronegative patient with untreated rheumatoid art 1997 May Pneumocystis carinii pneumonia (PCP) usually occurs in immunocompromised patients, and it is a life-threatening infection. We report the case of a human immunodeficiency virus (HIV)-seronegative patient with untreated rheumatoid arthritis (RA), who developed fatal PCP related to uncommon CD4+ T-lymphocytopenia. Although extremely rare and of uncertain aetiology, suppression of cellular immunity and subsequent opportunistic infections should be suspected in such patients.
9340204 [Ultrasound diagnosis of rheumatic/inflammatory joint diseases]. 1997 Jul Ultrasonography is an inexpensive and readily available imaging technology for joints and surrounding soft tissues. Examination usually requires only a few minutes, is safe and can be repeated frequently because no radiation is involved. The method depends much on the training and skills of the examiner and sonographic pictures should always be interpreted in context with history and clinical findings. Therefore, the same physician, who does the physical examination, should also perform the ultrasound. Then, this method has the potential to serve as the 'rheumatologist's extended finger'.
10509271 Wrist arthroplasty with a new generation of prostheses in patients with rheumatoid arthrit 1999 Sep The function of the wrist is frequently considerably impaired by early destruction in patients with rheumatoid arthritis. The aim of endoprosthetic arthroplasty is to restore functional use and provide freedom from pain. In our study a newly developed, uncemented wrist prosthesis was implanted in 30 patients (24 women and 6 men) with advanced destruction of the wrist. This wrist prosthesis is a hydroxyapatite-coated cobalt-chrome prosthesis with a titanium coating of the articular surfaces. The radial component has an articular surface inclination of 10 degrees toward the ulna, and the carpal component, which is anchored with its tip in the distal carpal bones and third metacarpal bone, has a double articular surface with a radial inclination of 10 degrees. At the 18-month follow-up visit, the following parameters were examined: x-ray, grip strength, range of motion, and the patient's subjective satisfaction. Good improvement of function was found in 92% of the patients; 87% were free of pain. Eighty-eight percent of the patients rated the outcome of surgery as good. If the indication is accurately diagnosed, this wrist prosthesis can markedly improve function, which in turn leads to high patient acceptance. Various salvage procedures remain open because of the minimal loss of bone stock and the uncemented implantation of the prosthesis.
9558162 Early radiographic joint space narrowing and erosion and later malalignment in rheumatoid 1998 Apr OBJECTIVE: To analyze the time course of development of radiographic erosion, joint space narrowing, and malalignment in a longitudinal study of radiographs of the hands and wrists of 58 patients with rheumatoid arthritis (RA) taken over 18 years. METHODS: Among 210 consecutive patients in a reported cohort, 58 had at least one prior available radiograph 2-18 years earlier. A total of 141 hand and wrist radiographs in the 58 patients were scored for joint space narrowing, erosion, and malalignment in individual joints. RESULTS: Of the 58 patients studied, all developed joint space narrowing, 56 (96.5%) developed erosions, while only 24 (41.4%) developed malalignment. In radiographs of 22 patient studied within the first 5 years of disease, joint space narrowing was seen in 17 (77.3%), erosion in 16 (72.7%), and malalignment in only 3 (13.6%). Radiographic progression was seen in all 36 patients in whom the interval between radiographs was longer than 2 years. CONCLUSION: Joint space narrowing and erosion are seen in hand radiographs of most patients with RA seen in treatment centers within the first 5 years of disease. By contrast, malalignment develops in fewer patients, and generally only after 5 years of disease.
10641509 [Rheumatoid arthritis: new molecular and cellular aspects]. 1999 Dec 15 BACKGROUND: Rheumatoid arthritis is a chronic systemic disorder of unknown etiology, that is characterized by inflammation, synovial hyperplasia and destruction of the affected joints. Novel molecular biology techniques have identified important cellular and molecular pathways in the pathogenesis of rheumatoid arthritis during the last years. RESULTS: The cellular activation of aggressively growing, matrix-degrading synovial fibroblasts is a key event in the pathogenesis of rheumatoid arthritis. The cellular activation results in an altered expression of apoptosis regulating molecules (for example CD 95 and Sentrin) as well as of protooncogenes (for example RAS and MYC). Important extracellular stimuli such as the pro-inflammatory cytokines interleukin-1 and TNF-alpha are overexpressed in the rheumatoid arthritis synovium. First clinical trials with cytokine inhibiting molecules (interleukin-1 receptor antagonist, recombinant soluble TNF-alpha receptor/Etanercept and monoclonal TNF-alpha antibodies/Remicade) revealed promising results. Etanercept is now available for the treatment of rheumatoid arthritis in the USA. In addition, gene transfer methods could help to overcome the problem of a continuous expression of therapeutic molecules in the affected joints; gene delivery of the interleukin-1 receptor antagonist is currently tested in a human trial. Finally, the inhibition of matrix degrading enzymes such as matrix metalloproteinases, that mediate the joint destructive features of the activated synovial fibroblasts, could be another therapeutic approach. CONCLUSIONS: The elucidation of important molecular and cellular pathways in the pathogenesis resulted in novel concepts in the therapy of rheumatoid arthritis. Gene transfer methods are of importance in studying the pathogenesis of the disease, however, their clinical safety and usefulness have to be proven in additional studies.
11053095 Arguments for interleukin 1 as a target in chronic arthritis. 2000 Nov Tumour necrosis factor (TNF) and interleukin 1 (IL1) are considered as master cytokines in chronic, destructive arthritis. Therapeutic approaches in rheumatic arthritis (RA) patients so far mainly focused on TNF. Although TNF is a major inflammatory mediator in RA and a potent inducer of IL1, anti-TNF treatment is not effective in all patients, nor does it fully control the arthritic process in affected joints of good responders. Analysis of cytokine patterns in early synovial biopsy specimens of RA patients reveals prominent TNF staining in 50% of the patients, whereas IL1b staining was evident in 100%. This argues that TNF independent IL1 production occurs in some of the patients. Studies in a range of experimental arthritis models in mice make it clear that TNF is involved in early joint swelling. However, TNF alone is not arthritogenic nor destructive and exerts its arthritogenic potential through IL1 induction. Intriguingly, TNF independent IL1 production is found in many models. Its relevance is further underlined by the greater efficacy of anti-IL1 treatment as compared with anti-TNF treatment and the total lack of chronic, erosive arthritis in IL1b deficient mice. IL1b is not necessarily involved in early joint swelling, but is a crucial mediator in chronic arthritis and cartilage erosion in all models studied so far. This makes ILb an attractive target in chronic, destructive arthritis.
10378705 A 12-month randomized controlled trial of patient education on radiographic changes and qu 1999 Apr OBJECTIVE: In rheumatoid arthritis, education programmes successfully impart knowledge but, notwithstanding issues of empowerment, this knowledge has to be translated into behavioural change to have a chance of improving disease outcome. Arguably, behavioural change must also occur early if outcomes are to be improved. For these reasons, we planned a study of patient education in early disease, with radiological damage and quality of life as the main outcome variables. METHODS: We performed a randomized controlled trial in people with rheumatoid arthritis of < 5 yr duration. The main intervention was a 4 week education programme, each weekly session lasting 2 h. Assessments were made at entry, at 4 weeks and at 12 months. The main outcome variables were the modified Larsen radiological score for the hands and the SF-36 quality of life questionnaire. Secondary outcome variables were the Health Assessment Questionnaire (HAQ), Ritchie Articular Index (RAI), Patient Knowledge Questionnaire (PKQ), Compliance Questionnaire (CQ), plasma viscosity (PV), pharmaceutical changes and consulting behaviour. RESULTS: The patient numbers were 34 (10 male, 24 female) for the control group and 43 (16 male, 27 female) for the education group. The groups were matched for age (56.5 yr for control, 55 yr for education), disease duration (3.5 yr vs 3.0 yr) and duration of second-line drug therapy (14 months vs 12 months). We found no significant difference between the groups for Larsen scores at 12 months, although scores for the education group were lower (39.5 vs 43.0, P = 0.13). The 'social functioning' and 'general health perception' subscales of the SF-36 showed a significant improvement in the education group, but no significant differences between groups were seen. No significant differences were found for the HAQ, RAI, PV and CQ, but the education group had more disease-specific knowledge than the control group at 12 months (PKQ scores: 17 vs 21, P = 0.0002). No differences were found for out-patient visits and in-patient admissions, but the education group had slightly more changes in second-line drugs during the study (0.43 changes/person in the control group, 0.51 changes/person in the education group). CONCLUSIONS: We found no significant difference between the groups in our primary outcome measures, but a trend in favour of the education group was found in radiological progression. Further studies of this kind, using larger patient numbers, are required since the difference may result from improved self-care, better compliance with joint protection strategies and, possibly, improved drug compliance.
11762258 [Sex differences in joint diseases: pathophysiological basis]. 2001 Gender affects the susceptibility to many joint diseases, in particular autoimmune rheumatic disorders; women have an increased risk of rheumatoid arthritis, systemic lupus erythematosus or Sjögren's syndrome. In rheumatoid arthritis alterations of sex hormone levels such as androgen deficiency or prolactin excess might, at least in part, explain the excess incidence in women. Osteoarthritis of the hand and the knee as well as generalized osteoarthritis is more frequent in women than in men. Nevertheless, until now there is no explanation for the increased incidence of osteoarthritis in women.