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ID PMID Title PublicationDate abstract
11302411 Etanercept in juvenile rheumatoid arthritis. 2001 Apr OBJECTIVE: To review the classification, pathophysiology, safety, and efficacy of treatment options for juvenile rheumatoid arthritis (JRA). Etanercept, the agent most recently approved by the Food and Drug Administration for use in JRA, is featured. DATA SOURCES: Articles were identified from a search of the MEDLINE database (1966 to January 2000) and through secondary sources. Meeting abstracts and posters were also evaluated. STUDY SELECTION AND DATA EXTRACTION: Articles identified and retrieved from data sources were evaluated and, if determined to be relevant, were included in this review. DATA SYNTHESIS: JRA represents a major cause of functional disability in children. In contrast to traditional therapeutic agents for JRA, which act through generalized antiinflammatory activity or generalized immunosuppression, new therapeutic modalities have been developed that target specific molecules involved in the pathophysiology of JRA. Etanercept inhibits the activity of tumor necrosis factor and lymphotoxin-alpha. In a clinical trial of patients with polyarticular-course JRA, etanercept-treated patients experienced less pain and swelling in their joints, decreased incidence of disease activity, less frequent flare, and a longer time to flare than patients receiving placebo. Treatment with etanercept was generally well-tolerated. CONCLUSIONS: Etanercept represents an exciting new therapeutic option for the treatment of JRA. The positioning of etanercept among other therapeutic options for JRA will be more clearly established as additional safety and efficacy data are made available.
11024553 Stress induces increases in IL-6 production by leucocytes of patients with the chronic inf 2000 Oct 2 Juvenile rheumatoid arthritis (JRA) is characterized by chronic inflammation of the joints. In the present study we demonstrate that exposure of JRA patients to a noradrenergic stressor (cold pressor test) results in enhanced LPS-induced IL-6 production by peripheral blood cells of these patients. Healthy, age-matched controls had the same rise in norepinephrine, but do not respond with changes in IL-6 production after exposure to the cold pressor test. Moreover, PBMC of patients with JRA express mRNA encoding alpha(1)-adrenergic receptors (AR), predominantly of the alpha(1d)-AR subtype. In contrast, we could not detect mRNA encoding for alpha(1)-AR in PBMC of healthy controls. The results of this study suggest that expression of alpha(1)-AR mRNA in PBMC during chronic inflammation is associated with altered responses of the immune system to stress.
9844775 Reduced levels of testosterone and dehydroepiandrosterone sulphate in the serum and synovi 1998 Nov OBJECTIVE: The status of androgen levels and their significance in the pathogenesis of juvenile rheumatoid arthritis (JRA) has not been fully investigated. In the present study serum and synovial fluid (SF) from 20 JRA patients (grouped as pre-pubertal and pubertal) were analyzed for their content of testosterone, dehydroepiandrosterone (DHEA) and its sulphated conjugate DHEA-S, progesterone and 17 beta-estradiol. RESULTS: Comparison of the results from JRA patients with that of age-matched controls indicated no significant differences in progesterone and DHEA. Similarly, 17 beta-estradiol levels from the pubertal group were comparable to those of the controls; however, prepubertal patients had no detectable levels of this hormone. DHEA-S values were significantly lower in the pubertal JRA group, 1388.3 +/- 291.8 and 1663.9 +/- 354.1 nmol/l in the serum and SF, respectively (compared to 8206.6 +/- 848.12 in the serum of matching controls). These patients also presented with a much lower testosterone content in their SF than in their serum, 0.09 +/- 0.036 and 0.56 +/- 0.068 nmol/l, respectively (compared to 1.35 +/- 0.146 in the serum of corresponding controls). CONCLUSION: The data presented in this paper demonstrate for the first time an association between low androgen levels and disease in JRA patients. The significance of hypoandrogenicity with respect to the pathogenic mechanisms of arthritic disease and the possible therapeutic strategies that these imply warrants further investigation.
9075699 Thyroxine administration prevents streptococcal cell wall-induced inflammatory responses. 1997 Apr Administration of streptococcal cell wall (SCW) preparation induces an inflammatory response in susceptible animals that is a model frequently used for rheumatoid arthritis. The degree of inflammation produced by SCW is greatly enhanced by low endogenous levels of glucocorticoids due to diminished hypothalamic-pituitary-adrenal activity. Because decreased glucocorticoid production is known to occur in the hypothyroid state, we tested whether hypothyroidism would increase, and conversely, whether hyperthyroidism would decrease, the inflammatory responses to SCW. Adult female Sprague Dawley rats were fed a regular diet (control), L-T4 (T4; hyperthyroid), or 6-propyl-thiouracil (hypothyroid) in drinking water for 7 weeks. Hypothyroidism resulted in elevated plasma levels of TSH and hypothalamic preproTRH messenger RNA (mRNA) while reducing anterior pituitary POMC mRNA and plasma ACTH and corticosterone levels. In contrast, hyperthyroid rats produced opposite results: decreased measures of central thyroid function but increased pituitary-adrenal function. Three days after administration of SCW, macrophage inflammatory protein-1alpha and interleukin-1beta mRNA expression increased dramatically in controls and even further in hypothyroid animals, as measured by Northern blot analysis. In contrast, T4-treated rats showed significant inhibition of these inflammatory markers. Thus, the hyperthyroid state combined with increased endogenous glucocorticoid levels is protective against inflammatory challenges. The inverse relationship between preproTRH expression and pituitary-adrenal function suggests the possibility of a direct inhibitory link connecting the hypothalamic-pituitary-adrenal and thyroid axes, and suggests alternative sites of therapeutic intervention for rheumatoid arthritis and other inflammatory associated disorders.
9608326 Novel therapeutic strategies involving animals, arthritis, and apoptosis. 1998 May Animal models of arthritis provide a window into the pathogenesis of inflammatory joint disease. In addition, they can function as an in vivo laboratory for evaluating new and creative treatments. The potential usefulness of novel treatment strategies, including recombinant cytokine therapy, gene delivery, and regulation of apoptosis, have been explored and offer clues to the feasibility of human therapeutic trials. New models of arthritis have also been developed in an effort to increase the predictive capacity for efficacy in rheumatoid arthritis.
11263765 Increased mortality in adults with a history of juvenile rheumatoid arthritis: a populatio 2001 Mar OBJECTIVE: To assess mortality in a population-based cohort of adults with a history of juvenile rheumatoid arthritis (JRA). METHODS: The Rochester Epidemiology Project database was used to identify all cases of JRA diagnosed among Rochester, Minnesota residents under the age of 16 between January 1, 1960 and December 31, 1993. Fifty-seven patients in this cohort are now adults (ages 18-53 years, mean age 34.3 years), and this subgroup was contacted for a long-term followup study. The average length of followup from the time of diagnosis was 25.6 years. RESULTS: Four deaths occurred in this cohort of 57 adults with a history of JRA. All 4 deceased patients had other autoimmune illnesses and died of complications of these diseases. The observed frequency of 4 deaths was significantly greater (P < 0.0026 by one-sample log-rank test) than the 1 death that would be expected among Minnesota whites of similar age and sex, and corresponds to a mortality rate of 0.27 deaths per 100 years of patient followup compared with an expected mortality rate of 0.068 deaths per 100 years of followup in the general population. CONCLUSION: The results indicate a significant, unexpected increase in mortality in this population-based cohort of adults with a history of JRA in comparison with the rate in the general population. The deaths in this group were all associated with other autoimmune disorders, suggesting that special emphasis should be given to the diagnosis and treatment of other autoimmune diseases, including immunodeficiencies, in JRA patients. The frequency of deaths in this cohort suggests that JRA patients are at substantial risk for mortality, and highlights the need for longitudinal followup and care into adulthood.
11067961 Antigen-specific T cells transduced with IL-10 ameliorate experimentally induced arthritis 2000 Nov 15 For the treatment of rheumatoid arthritis, efficient drug delivery methods to the inflamed joints need to be developed. Because T cells expressing an appropriate autoantigen-specific receptor can migrate to inflamed lesions, it has been reasoned that they can be employed to deliver therapeutic agents. To examine the ability and efficiency of such T cells as a vehicle, we employed an experimentally induced model of arthritis. Splenic T cells from DO11.10 TCR transgenic mice specific for OVA were transduced with murine IL-10. Adoptive transfer of the IL-10-transduced DO11.10 splenocytes ameliorated OVA-induced arthritis despite the presence of around 95% nontransduced cells. Using green fluorescent protein as a marker for selection, the number of transferred cells needed to ameliorate the disease was able to be reduced to 10(4). Preferential accumulation of the transferred T cells was observed in the inflamed joint, and the improvement in the disease was not accompanied by impairment of the systemic immune response to the Ag, suggesting that the transferred T cells exert their anti-inflammatory task locally, mainly in the joints where the Ag exists. In addition, IL-10-transduced DO11.10 T cells ameliorated methylated BSA-induced arthritis when the arthritic joint was coinjected with OVA in addition to methylated BSA. These results suggest that T cells specific for a joint-specific Ag would be useful as a therapeutic vehicle in rheumatoid arthritis for which the arthritic autoantigen is still unknown.
9488400 Biased T-cell antigen receptor repertoire in Lyme arthritis. 1998 Mar A common concern with many autoimmune diseases of unknown etiology is the extent to which tissue T-lymphocyte infiltrates, versus a nonspecific infiltrate, reflect a response to the causative agent. Lyme arthritis can histologically resemble rheumatoid synovitis, particularly the prominent infiltration by T lymphocytes. This has raised speculation about whether Lyme synovitis represents an ongoing response to the causative spirochete, Borrelia burgdorferi, or rather a self-perpetuating autoimmune reaction. In an effort to answer this question, the present study examined the repertoire of infiltrating T cells in synovial fluid from nine Lyme arthritis patients, before and after stimulation with B. burgdorferi. Using a highly sensitive and consistent quantitative PCR technique, a comparison of the T-cell antigen receptor (TCR) beta-chain variable (Vbeta) repertoires of the peripheral blood and synovial fluid showed a statistically significant increase in expression of Vbeta2 and Vbeta6 in the latter. This is remarkably similar to our previous findings in studies of rheumatoid arthritis and to other reports on psoriatic skin lesions. However, stimulation of synovial fluid T cells with B. burgdorferi provoked active proliferation but not a statistically significant increase in expression of any TCR Vbeta, including Vbeta2 and Vbeta6. Collectively, the findings suggest that the skewing of the TCR repertoire of fresh synovial fluid in Lyme arthritis may represent more a synovium-tropic or nonspecific inflammatory response, similar to that occurring in rheumatoid arthritis or psoriasis, rather than a specific Borrelia reaction.
9588736 Lack of correlation between the detection of Chlamydia trachomatis DNA in synovial fluid f 1998 May OBJECTIVE: To resolve how frequently Chlamydia trachomatis and Chlamydia pneumoniae DNA are present in the joints of unselected patients with reactive arthritis (ReA) and undifferentiated oligoarthritis, and to determine if there is an accompanying serologic or cellular antichlamydial immune response. METHODS: Two polymerase chain reaction (PCR) protocols to detect the plasmid of C. trachomatis and the outer membrane protein 1 gene of C. pneumoniae were developed for specific use with synovial fluid (SF). Subsequently, the assays were used to detect DNA from the 2 organisms in SF from 54 adult patients with rheumatic diseases, including 4 with sexually acquired ReA and 31 with undifferentiated oligoarthritis. The presence of chlamydial antibodies and SF lymphocyte proliferation responses were determined in parallel. RESULTS: The PCR protocols were species-specific and highly sensitive. SF samples from 15 patients (8 with undifferentiated oligoarthritis, 3 with ReA, 1 with rheumatoid arthritis, and 1 with psoriatic arthritis) were positive for C. trachomatis. There was no significant correlation between the presence of C. trachomatis DNA in the joint and a Chlamydia-specific synovial T cell response or a serologic response. C. pneumoniae was not detected in any of the 54 patients, although it was identified in the SF from a rheumatoid arthritis patient outside this study, demonstrating that the assay was capable of detecting the organism in the joint. CONCLUSION: C. trachomatis DNA was present in ReA patients and in nearly one-third of unselected patients with undifferentiated oligoarthritis, which further supports the hypothesis that it plays an important role in disease pathogenesis. However, its presence did not correlate with evidence of an antichlamydial immune response. Despite previous anecdotal reports, C. pneumoniae does not appear to be a major cause of undifferentiated oligoarthritis or ReA.
10556272 Remission of inflammatory arthropathy in association with anti-CD20 therapy for non-Hodgki 1999 Nov We describe a case involving a 53-yr-old male with a marginal zone B-cell lymphoma, associated with an IgM paraprotein and a rheumatoid factor-negative inflammatory polyarthropathy, treated with monoclonal anti-CD20 antibody. During the subsequent 12 weeks, evidence of synovitis reduced to a negligible level, despite no significant change in lymphoma bulk or paraprotein level. The relationship between the lymphoma and the arthropathy, and the likely mechanism of remission of the arthropathy, are discussed in the context of the potential value of anti-CD20 therapy in rheumatoid arthritis.
11560160 Chronic tophaceous gout presenting as hyperpigmented nodules in the limbs of a patient wit 2001 Aug We describe a 53-year-old male renal transplant recipient with hypertension and triglyceridemia, who showed rare manifestations of gout presenting as brownish nodules on the arms and legs as well as chronic tophaceous gouty arthritis of the hands and feet mimicking rheumatoid arthritis, in association with subsequently developed psoriasis of the palms. In elderly Asian men, hypertension and renal insufficiency may be risk factors predisposing to the development of multiple hyperpigmented nodules of tophi in the more proximal extremities.
10083958 Causes of pain in children with arthritis. 1999 Feb Pain in children with juvenile rheumatoid arthritis (JRA) is often not fully recognized and is therefore incompletely treated. The use of pain assessment instruments developed specifically for children may enhance recognition by health care providers. Recent studies suggest that coping variables and disease severity are significant predictors of pain in children with JRA. Pain in children with JRA is a complex phenomenon, best managed using a multidisciplinary approach that includes aggressive traditional medical management and addresses psychosocial variables such as coping strategies and perceptions about disease.
11529930 The genetic and immunopathological processes underlying collagen-induced arthritis. 2001 Aug Animal models of rheumatoid arthritis (RA) have provided substantial insights into basic pathogenic mechanisms of chronic inflammatory arthritis and autoimmune disease in general. Of the variety of models reported, collagen-induced arthritis (CIA) has been the most characterized in terms of both its pathogenesis and its underlying immunological basis. Collagen-induced arthritis has also been the model of choice in terms of testing potential new therapeutic agents for the treatment of human RA. Nevertheless, the complex nature of the balance between T-cell cytokines and the chronic inflammatory processes is only recently becoming clear. This review focuses on these developments, highlighting their implications for our understanding of RA and for the use of CIA as a suitable animal model.
9453202 [Inflammatory amyloidosis]. 1997 Oct 15 Inflammatory amyloidosis consists of AA protein. In developed countries, its predominant causes are chronic inflammatory rheumatism (rheumatoid arthritis, chronic juvenile arthritis, spondylarthropathy, etc.). More rare are other chronic inflammatory disorders (Crohn's disease, ulcerative colitis, Whipple's disease, etc.), hemopathies and neoplasia. In developing countries, infectious causes are the most common (tuberculosis, leprosy, chronic bacterial suppuration). Other infectious diseases complicated with amyloidosis are less common (bronchial dilatation, mucoyiscidosis, heroin injection-related skin suppuration). In chronic infection, amyloidosis is observed a mean of 10 years after the beginning of the triggering disorder and is mainly localised in the kidney, the liver and the gastrointestinal tract. The course is most often slow and prolonged survival has been reported.
19078386 The effectiveness of the clinical self-assessment (MHAQ) compared with other clinical and 1999 Aug Disease activity in rheumatoid arthritis (RA) is difficult to measure objectively. Both clinical and laboratory measures were evaluated by the statistical method of consensus analysis. In the literature, laboratory tests as a group have proved more effective; however, studies did not include self-assessment questionnaires. We evaluated the effectiveness of a Modified Health Assessment Questionnaire (MHAQ) relative to other clinical and laboratory tests measuring disease activity in 100 patients with RA. Hemoglobin, hematocrit, mean corpuscular volume, fibrinogen level, Wes-tergren erythrocyte sedimentation rate and C-reactive protein tests, along with tests of morning stiffness, visual analog pain scale, Ritchie index, total joint count, and MHAQ, were evaluated simultaneously. The erythrocyte sedimentation rate was confirmed as a highly effective test to follow disease activity. The MHAQ was the best clinical test; in the methotrexate-treated subgroup it ranked as highly as the most effective laboratory assays. MHAQ is a more effective tool than many laboratory tests currently ordered for monitoring RA disease activity and should be a part of the record of each visit of an arthritis patient.
11127581 Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis. 2000 Nov Immunomodulation of autoimmune inflammatory diseases like rheumatoid arthritis can be achieved by anti-inflammatory T2 cytokines such as interleukin (IL)-4 administered by gene therapy. In this study we investigated the efficiency of adeno-associated viruses (AAV) vectors in collagen-induced arthritis (CIA). After injection of AAV-LacZ in the tarsus area of mice, the expression of the transgene was localized in the deep muscles cells near the bone. LacZ expression was found in liver, heart and lung after i.m. injection of AAV-LacZ, showing a spread of the vector over the body. Anti-AAV neutralizing antibodies were detected in the serum after i.m. injection of AAV-LacZ, but they did not alter the transgene expression after re-administration of AAV-LacZ. Long-term IL-4 expression persisted 129 days after intra-muscular injection of 3.7 x 10(10) or 11.2 x 10(10) AAV-IL-4 p.p. (average 7.7 or 17.5 pg IL-4/mg proteins, respectively). More importantly, the treatment of CIA with AAV-IL-4 vector in mice produced a therapeutic benefit, since we show a diminished prevalence of the disease, a significant reduction in paw swelling, attenuated histological synovitis and a 10 days delayed onset of arthritis. This is the first evidence that AAV vector-mediated gene therapy using a T2 cytokine is efficient in an animal model of rheumatoid arthritis.
11770391 Immunomodulating drugs in the management of psoriatic arthritis. 2001 Psoriatic arthritis is a chronic inflammatory arthropathy which can be distinguished from rheumatoid arthritis on the basis of differing patient demographics, genetic predisposition, histopathologic change, radiographic appearance, and clinical course. The cause of psoriatic arthritis remains unknown but appears to be autoimmune in nature as its pathogenesis is characterized by persistent synovial inflammation resulting in damage to the articular cartilage and osteolysis. Compared with rheumatoid arthritis, distinct lymphocyte subpopulations and pro-inflammatory cytokine levels appear to be present within the joint but the importance and therapeutic implications of these differences is uncertain. The clinical presentation of psoriatic arthritis is variable and overlapping patterns of joint involvement affecting both the appendicular and axial skeleton are seen. For patients with mild synovial disease and a favorable prognosis, the use of a nonsteroidal anti-inflammatory drug for symptomatic relief is often sufficient. However, the destructive potential of psoriatic arthritis is increasingly recognized and patients with more synovial disease and radiographic change at presentation appear to be at risk for greater morbidity and increased mortality. Immunomodulating therapy has the potential to suppress joint inflammation and preserve functional capacity but true disease modification has yet to be shown. The toxicity associated with presently available immunomodulatory agents makes careful patient selection and conscientious monitoring essential. The efficacy of methotrexate and sulfasalazine in patients with psoriatic arthritis is well defined while more anecdotal reports of benefit exist for other agents including the antimalarials, azathioprine, colchicine, cyclosporine, and the retinoids. For all treatment regimens, the magnitude of clinical improvement demonstrated to date has been rather small and quite subjective in character with few controlled studies of adequate size and duration having been reported. Emerging biologic therapies, such as those which target tumor necrosis factor, will hopefully provide future treatment options with greater efficacy and improved safety for patients with psoriatic arthritis.
11138599 Are rofecoxib and celecoxib safer NSAIDS? 2000 Nov NSAIDs work by inhibiting the enzyme cyclo-oxygenase (COX), responsible for prostaglandin synthesis. This enzyme exists in two isoforms, COX-1 and COX-2. Inhibition of COX-1 is thought to be the main cause of the gastrointestinal unwanted effects of NSAIDs, whilst inhibition of COX-2 results in anti-inflammatory effects. [symbol: see text]Rofecoxib (Vioxx--MSD) and [symbol: see text]celecoxib (Celebrex--Searle) have been developed as selective inhibitors of COX-2. Rofecoxib is licensed for the symptomatic treatment of osteoarthritis, but not for rheumatoid arthritis. The manufacturer claims that "in clinical studies rofecoxib inhibits COX-2 but not COX-1", has "the power of high-dose NSAIDs--diclofenac and ibuprofen" and "superior GI safety profile compared to conventional NSAIDs". Celecoxib is licensed for symptom relief in osteoarthritis and rheumatoid arthritis. The manufacturer claims that celecoxib has "comparable efficacy and superior GI tolerability when compared to diclofenac or naproxen". Here, we review rofecoxib and celecoxib and consider whether they are safer than conventional NSAIDs.
9930004 [Hypertransaminemia and methotrexate: not always a toxic effect?]. 1998 Dec Serial measurement of liver enzymes is useful to detect liver toxicity due to methotrexate in patients with rheumatoid arthritis or other rheumatic diseases. We have reviewed retrospectively 141 adult patients treated with methotrexate from 1988 to 1991. The more common diagnoses included rheumatoid arthritis (120 cases) and psoriatic arthritis (12 cases). In periodic studies carried our every 2-3 months, a transient increase in transaminase values associated with methotrexate in 13 patients (9.2%) was observed. Two patients developed a viral infection during therapy, one due to cytomegalovirus and the other due to the Epstein-Barr virus. Both patients had a favorable outcome once methotrexate was withdrawn.
9483913 [Clinical course and prognostic parameters in adult-onset Still's syndrome. Own experience 1997 Dec 15 PATIENTS AND METHODS: Ten patients with adult onset of Still's disease (AOSD) were examined one to nine years after the established diagnosis. Clinical symptoms, laboratory parameters and the outcome of the cases are presented and compared to international literature and to Yamagushi's in 1992 proposed diagnostic criteria. Nine patients were reexamined in our out-patient clinic. The chart of one additional patient, who died 10 month after the initial symptoms was also available for data analysis. Retrospectively, it was investigated whether any parameters were predictive for a chronic or severe form of the disease. RESULTS: One patient died 10 month after the diagnosis was established due to a secondary haemophagozytic syndrome. One patient developed a chronic form of the disease, whereas 2 patients had a chronic-remitting form. Six patients presented a self-limiting, shorter than 12 month lasting course of AOSD with a restitutio ad integrum. All patients fulfilled the diagnostic criteria of Yamagushi et al. Three of 10 patients developed a chronic form of AOSD, compared to up to 70% of the patients reported by others. The patient who died was significantly older (46 years) than the average age (24,9 years) of all patients. Interestingly, he did not present Still's rash or lymphadenopathy, but rather developed a secondary hemophagocytic syndrome with an excessive hyperferritinaemia. CONCLUSION: Predicting parameters for a chronic course of the disease could not be found. Each patient's diagnosis retrospectively could be confirmed using the Yamagushi's diagnostic criteria. Thus, these criteria appear helpful in the difficult diagnostic process of this disease.