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ID PMID Title PublicationDate abstract
1450796 Upper gastrointestinal complaints and complications in chronic rheumatic patients in compa 1992 Nov The aim of this study was to compare the frequency of upper gastrointestinal (GI) complaints and complications between chronic rheumatic patients who are most often non-steroidal anti-inflammatory drugs (NSAIDs) users and patients with other chronic conditions. In this comparison we took into account known risk factors for upper GI disease. To achieve the study aims we performed a combined cross-sectional and retrospective study. We therefore interviewed by means of a standard questionnaire, an index and a reference group, about current upper GI complaints and previous complications. The former group comprises 578 outpatients of the Department of Rheumatology, the latter of 531 outpatients of the Departments of Internal Medicine, Pulmonology, and Cardiology. Although the number of patients in the index group being chronically treated with NSAIDs was very high (62% versus 9% in the reference group: P < 0.00001), no between-group differences were found for the frequency of several current upper gastrointestinal complaints or for the number of upper gastrointestinal investigations ever performed (35% and 37%: NS) or for the use of gastric drugs (14% and 10%: NS). Risk factors for upper GI complaints were not related to NSAID use but with the use of prednisolone, history of duodenal ulcer disease, family history of peptic ulcer disease and female sex. For peptic ulcer disease, bleeding, and gastric surgery, the only difference between the index and reference groups concerned the frequency of gastric ulcers (6.7% and 2.8%: P < 0.005), which was highest in patients with rheumatoid arthritis. Upper GI bleeding had more often been present in male seropositive rheumatoid arthritis patients (13.2% [corrected] and 4.5%: P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
7944079 The role of leukotrienes in inflammation. 1994 Nov 1 OBJECTIVE: To review the biochemistry and biological activities of leukotrienes, focusing on their role in the mediation of inflammatory diseases. DATA SOURCES: MEDLINE (1966-1994), EMBASE (Excerpta Medica; 1974-1994), and other biomedical and drug directory databases (such as Pharmaprojects and IMSworld R&D Focus [1991-1994]) were searched to identify English-language articles (basic science, clinical trial research, and review articles) and abstracts of conference proceedings on leukotrienes and related terms. STUDY SELECTION: Basic science studies on leukotrienes and clinical research studies on the use of leukotriene inhibitors and antagonists in the treatment of inflammatory diseases such as asthma, psoriasis, rheumatoid arthritis, and ulcerative colitis. DATA EXTRACTION: Detailed summaries of data from basic science studies on the formation and actions of leukotrienes and from clinical studies of drugs that block the synthesis or receptor-mediated actions of leukotrienes. DATA SYNTHESIS: Leukotrienes are biologically active 5-lipoxygenase products of arachidonic acid metabolism that are involved in the mediation of various inflammatory disorders. Of these, leukotriene B4 (a potent chemoattractant for leukocytes) and the sulfidopeptide leukotrienes C4, D4, and E4 (which increase vascular permeability and constrict smooth muscle) exert their biological actions through specific ligand-receptor interactions. Selective leukotriene inhibitors and receptor antagonists are currently under evaluation in the treatment of various inflammatory diseases. CONCLUSIONS: Further data on the in vitro and in vivo activities of the leukotriene inhibitors and antagonists should clarify the role of leukotrienes in the pathogenesis of such inflammatory diseases as asthma, rheumatoid arthritis, and inflammatory bowel disease. Leukotriene inhibitors and antagonists will probably become important agents in the group of anti-inflammatory drugs.
8552648 Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonis 1996 Jan 9 Restoration of the impaired balance between pro- and antiinflammatory cytokines should provide effective treatment of rheumatoid arthritis. Gene therapy has been proposed as an approach for delivery of therapeutic proteins to arthritic joints. Here, we examined the efficacy of antiinflammatory gene therapy in bacterial cell wall-induced arthritis in rats. Human secreted interleukin 1 receptor antagonist (sIL-1ra) was expressed in joints of rats with recurrent bacterial cell wall-induced arthritis by using ex vivo gene transfer. To achieve this, primary synoviocytes were transduced in culture with a retroviral vector carrying the sIL-1ra cDNA. Transduced cells were engrafted in ankle joints of animals prior to reactivation of arthritis. Animals in control groups were engrafted with synoviocytes transduced with lacZ and neo marker genes. Cells continued to express transferred genes for at least 9 days after engraftment. We found that gene transfer of sIL-1ra significantly suppressed the severity of recurrence of arthritis, as assessed by measuring joint swelling and by the gross-observation score, and attenuated but did not abolish erosion of cartilage and bone. The effect of intraarticularly expressed sIL-1ra was essentially local, as there was no significant difference in severity of recurrence between unengrafted contralateral joints in control and experimental groups. We estimate that locally expressed sIL-1ra was about four orders of magnitude more therapeutically efficient than systemically administered recombinant sIL-1ra protein. These findings provide experimental evidence for the feasibility of antiinflammatory gene therapy for arthritis.
9038666 Interleukin 10 suppresses experimental chronic, granulomatous inflammation induced by bact 1996 Dec BACKGROUND AND AIMS: Interleukin 10 (IL10) inhibits monocyte/macrophage and T lymphocyte effector functions. This study examined the effect of systemically administered IL10 on acute and chronic granulomatous enterocolitis, hepatitis, and arthritis in a rat model. METHODS: Lewis rats were injected intramurally with streptococcal peptidoglycan-polysaccharide (PG-APS) polymers. Beginning 12 hours before PG-APS injection, rats were treated daily with subcutaneous murine recombinant IL10 or vehicle for three or 17 days. RESULTS: IL10 attenuated acute enterocolitis in a dose dependent fashion (p < 0.01). Protective effects were more profound in the chronic granulomatous phase with decreased enterocolitis and markedly inhibited leucocytosis, hepatic granulomas, and chronic erosive arthritis (p < 0.001). IL10 downregulated tissue IL1, IL6, tumour necrosis factor alpha, and interferon gamma gene expression, consistent with the in vitro effects of IL10 on PG-APS-stimulated splenocytes. Caecal IL1 protein concentrations and IL2 and interferon gamma secretion by in vitro stimulated mesenteric lymph nodes were downregulated in IL10 treated animals. CONCLUSIONS: These results indicate that exogenous IL10 can inhibit experimental granulomatous inflammatory responses and suggest that IL10 treatment could be an effective new therapeutic approach in human disorders such as Crohn's disease, rheumatoid arthritis, and sarcoidosis.
7898656 Spinal prodynorphin gene expression in collagen-induced arthritis: influence of the glucoc 1994 Nov Changes in the spinal expression of the opioid precursor and prodynorphin, which has been implicated in the response to peripheral inflammation, were examined with semi-quantitative in situ hybridization histochemistry in rats subjected to collagen II-induced arthritis. The effects of glucocorticosteroid treatment on the basal and inflammation-induced prodynorphin expression were evaluated. Collagen II-induced arthritis caused a 16-fold increase in prodynorphin mRNA levels which comprised all neurons expressing low levels under normal conditions. In the superficial dorsal horn, one group of neurons of a large size reacted with a dramatic increase of prodynorphin mRNA, while another group of small neurons exhibited a moderate elevation of prodynorphin mRNA levels. In the deep dorsal horn of arthritic rats, most prodynorphin neurons were large and showed high prodynorphin mRNA levels. Systemic treatment with the glucocorticosteroid budesonide attenuated the arthritis-induced increase of prodynorphin mRNA expression in a topospecific manner. The budesonide-induced reduction of prodynorphin mRNA levels was more pronounced in the deep dorsal horn than in the superficial dorsal horn. Budesonide treatment of control animals caused a small, but significant increase in prodynorphin mRNA levels in the superficial laminae I/II without affecting prodynorphin mRNA levels in the deep dorsal horn. The degree of arthritis correlated closely with spinal prodynorphin mRNA levels. The tight correlation between severity of arthritis and prodynorphin mRNA levels in non-treated and corticosteroid-treated arthritic rats suggests that spinal prodynorphin expression is a good parameter for the evaluation of the influence of peripheral inflammation and of the efficacy of analgesic/anti-inflammatory drugs in its treatment. Opposite effects of budesonide on basal and inflammation-induced prodynorphin expression may involve a spinal site of action in addition to peripheral anti-inflammatory mechanisms. We suggest that the collagen II-induced arthritis in the rat is an excellent model for human rheumatoid arthritis allowing for the study of molecular plasticity of anti-inflammatory and anti-nociceptive drug action at different levels of the neuroaxis.
8851203 [The clinical significance of the measurement of serum soluble interleukin-2 receptors in 1996 Feb We measured the serum levels of soluble interleukin-2 receptor (sIL-2R) in patients with collagen disease, viral hepatitis, and chronic renal failure on hemodialysis (HD) by enzyme immunoassay. sIL-2R levels were significantly higher in patients with collagen diseases (rheumatoid arthritis (RA), 843 +/- 509; systemic lupus erythematosus (SLE), 774 +/- 308; Sjögren's syndrome (SjS), 760 +/- 288; progressive systemic sclerosis (PSS), 649 +/- 198U/ml), with the viral markers of hepatitis B or C (HBsAg positives, 911 +/- 589; anti-HCV positives, 664 +/- 455U/ml) or with chronic renal failure on HD(1,431 +/- 406U/ml) than in the controls (302 +/- 57U/ml). In RA patients, there was a significant positive correlation between sIL-2R level and Lansbury's Indice or serum rheumatoid factor level. Patients with viral hepatitis showed a significantly positive correlation between the sIL-2R level and the level of ZTT or TTT. There was a significant difference between the HD patients with the anti-HCV antibody and those without, and between those with the anti human T lymphotrophic virus-I (HTLV-I) antibody and those without. In addition, there was a significant positive correlation between the sIL-2R level and duration of HD. These findings suggest that sIL-2R is a useful marker for disease activity in collagen diseases, especially in RA, and chronic viral infection such as HBV, HCV or HTLV-I in HD patients.
1279899 Molecular mimicry--hypothesis or reality? 1992 Aug A number of observations support molecular mimicry as a possible pathogenetic mechanism in diseases such as acute rheumatic fever, reactive arthritis after enteric infection or associated with Reiter's syndrome, myasthenia gravis, or even in rheumatoid arthritis. Molecular mimicry can be defined as a sharing of epitopes in linear or 3-dimensional presentation on disparate proteins from entirely different sources--for instance, group A streptococcal membranes and human cardiac myosin. How exposure to or infection with organisms sharing molecular similarity with antigens of the human host can evade tolerance and actually induce a self-reacting humoral or cellular immune response is still not clear; however, a large body of evidence has now been accumulated that documents apparent molecular mimicry mechanisms in these disorders. In some diseases, the molecular mimicry appears to involve human target organs and specific components of the infectious organism, whereas in others the host HLA cell surface molecules appear to share antigens with presumed bacterial or viral initiators of disease.
8782142 The Juvenile Arthritis Functional Status Index (JASI): a validation study. 1996 Jun OBJECTIVE: To evaluate aspects of reliability and validity of the Juvenile Arthritis Functional Status Index (JASI). We developed this questionnaire to assess a variety of daily living and functional mobility tasks in children with juvenile rheumatoid arthritis (JRA). JASI part I consists of 100 functional items divided into 5 activity categories (self-care, domestic, mobility, school, extracurricular). A 7 point degree of difficulty rating scale is used for responses. JASI Part II is a priority function section within which the child identifies and scores important activities for improvement. METHODS: The JASI was administered to 30 children with JRA 8 to 19 years of age at baseline, 3 weeks, and 3 months to determine test-retest reliability. Various rheumatology measures were used to evaluate the JASI construct validity. RESULTS: Reliability of JASI Part I was excellent (intraclass correlation coefficients > or = 0.95) for both retest intervals. Reliability was lower for respondents with mild disease than those with polyarticular disease. JASI Part I scores correlated strongly with rheumatology measures including joint count, grip strength, hip synovitis, timed walk and run. ACR functional class, and range of motion (r > 0.50), indicating construct validity. There was fair to good agreement between scores from the child's self-report and those from therapist observation of the child's abilities on the same activities. This provides evidence that children as young as 8 years of age can realistically report on function on their own. In JASI Part II, respondents identified a mean of 5.9 functional items in the baseline priority activity list. Test-retest reliability for JASI Part II was fair (kappa = 0.57). Further work is needed to determine the most reliable and sensitive response sequence for evaluating change in priority functions with JASI Part II. CONCLUSION: JASI Part I is a reliable and valid functional measure for school age children and adolescents with JRA. Research is under way to evaluate responsiveness to change. Comparisons will be made with shorter JRA functional measures to determine differences in sensitivity.
8935166 Synthesis of alpha-glucosidase I inhibitors showing antiviral (HIV-1) and immunosuppressiv 1996 Feb The synthesis of a series of analogues of the monosaccharide alpha-glucosidase I inhibitor N-decyl-1-deoxynojirimycin (1) is described. With the incorporation of a single oxygen atom particularly at position seven in the N-decyl side chain, i.e. to give N-7-oxadecyl-dNM (4), the therapeutic ratio (alpha-glucosidase I inhibitory activity over toxicity in HepG2 cells) increases considerably. N-7-Oxadecyl-dNM inhibits purified porcine liver alpha-glucosidase I with an IC50 value of 0.28 microM. The position of the oxygen atom in the N-decyl side chain is of importance since N-3-oxadecyl-dNM is less active and, moreover, is toxic to HepG2 cells at 3 mM. Subsequently, the synthesis of a disaccharide inhibitor of alpha-glucosidase I is described. The aminodisaccharide ManNH2 alpha 1,2Glc (12) inhibits alpha-glucosidase I with an IC50 value of 15.7 microM. Two closely related monosaccharide derivatives of 12 did not inhibit the enzyme at low microM concentrations (no inhibition at 5 microM), showing the additional effect of binding of the aglycon fragment of the molecule to the active site of alpha-glucosidase I. Next, the N-alkyl-dNM derivatives were analysed for antiviral and immunomodulatory activity in-vitro. It is found that the most potent alpha-glucosidase I inhibitor from this study, N-7-oxadecyl-dNM (4) inhibits HIV-1 induced syncytia formation and lymphocyte proliferation in-vitro. Finally, compound 4 was also investigated in-vivo. N-7-Oxadecyl-dNM (4) reduced adjuvant-induced arthritis in rats making this compound a potential candidate for treating autoimmune diseases like rheumatoid arthritis.
8546745 Cross-cultural adaptation of a brief outcome questionnaire for Spanish-speaking arthritis 1996 Jan OBJECTIVE: To cross-culturally adapt a brief self-assessment questionnaire to measure outcome among English- or Spanish-speaking patients with arthritis. METHODS: A questionnaire containing the following items was translated to Spanish: the 8 activities of daily living (ADL) question of the Modified Health Assessment Questionnaire; a question about the duration of morning stiffness; and a 10-point pain scale. Equivalence to the original English, test-retest reliability, and construct, criterion, and discriminant validity were determined on a population of patients with 4 clinical centers. RESULTS: English-Spanish equivalence and test-retest reliability of the questionnaire were almost perfect (intra-class correlation coefficients [ri] > or = 0.90 for each). Construct validity, measured by comparing questionnaire scores with an occupational therapist's evaluation, was also near-perfect in both languages (ri = 0.93 for English and 0.89 for Spanish). Both versions of the questionnaire correlated well with the physician-determined Steinbrocker functional class, as well as with the amount of pain, grip strength, and walking velocity. Patients with systemic lupus erythematosus, rheumatoid arthritis, osteoarthritis, and fibromyalgia differed significantly in their pain:ADL ratios, in both languages. CONCLUSIONS: The items of the Spanish questionnaire that we have adapted are equivalent to the original English versions. This questionnaire is suitable for studying Spanish-speaking subjects with arthritis in the US and elsewhere.
7983664 Demography of a regional pediatric rheumatology patient population. Affiliated Children's 1994 Aug OBJECTIVE: To examine the descriptive epidemiology of a regional cohort of children with rheumatic disease, and to document the variety and frequency of diseases encountered among pediatric rheumatology centers. METHODS: Pediatric rheumatology centers in southern New England participated in a prospective multicenter patient registry. All outpatients attending clinics at 8 pediatric rheumatology centers were enrolled as subjects during the 8-year period of study (n = 4585). Diagnostic criteria defined the rheumatic disease cases which were determined by clinical examination by a pediatric rheumatologist, and record linkage was achieved to avoid duplication of subjects. RESULTS: Rheumatic conditions were diagnosed in 1742 subjects. Juvenile rheumatoid arthritis (JRA) was the most frequently encountered rheumatic condition (53%), followed by spondyloarthropathy syndromes (13%), vasculitis (10%), systemic lupus erythematosus (SLE) (6%), isolated Raynaud's phenomenon (5%), dermatomyositis/polymyositis (DM/PM) (5%), and scleroderma (2%). The mean annual incidence of JRA, spondyloarthropathy syndromes, SLE and DM/PM among children referred to pediatric rheumatology centers in Massachusetts was 4.0, 2.0, 0.4 and 0.4 per 100,000 children at risk, respectively. Nonrheumatic conditions were diagnosed in 2843 subjects, among which musculoskeletal conditions were most frequent (56%) followed by infectious disorders (18%), psychogenic disorders (3%), fever of unknown origin (2%), and abnormal immune serology without a specific diagnosis (2%). CONCLUSION: The use of a multicenter patient registry was successful in allowing the collection of descriptive epidemiologic data on a large and well defined sample of children with rare disorders.
7511076 Adhesion of peripheral blood lymphocytes of children with arthritis to human umbilical vei 1994 Mar To determine whether adhesion of peripheral blood lymphocytes (PBL) of patients with juvenile rheumatoid arthritis (JRA) may be enhanced, adhesion of PBL of children with JRA, children with seronegative spondyloarthropathies (SSA), age-appropriate and adult controls, to human umbilical vein endothelial cells (HUVEC) was assessed in vitro. B and CD4 T lymphocytes in initial, adherent, and non-adherent cell fraction were identified by flow cytometry. B lymphocytes of all the younger subjects combined had a higher adherence to activated HUVEC compared with B lymphocytes of the adult donors. Except for greater adherence of HLA-DR+ CD4 T cells, lymphocytes of children with JRA showed no enhanced adhesion to either unactivated or activated HUVEC. The percentage of B cells adherent to activated HUVEC in each of the subject groups was 1.5-3.6-fold higher than adherent CD4 T lymphocytes. Surface analyses indicated higher percentages of CD49d (alpha 4)+ and CD29 (beta 1)+ CD4 T lymphocytes in adherent cells, but less of a differential in CD49 (alpha 4)+ and no difference in CD29 (beta 1)+ B lymphocytes. There were fewer Leu-8 (L-selectin)+ B and Leu-8+ CD4 T cells among adherent cells. The data suggest a greater adhesive capacity of B lymphocytes compared with CD4 T lymphocytes which is unrelated to disease, and the possibility that B lymphocytes may utilize adhesion molecules distinct from those of CD4 T lymphocytes. Only a small subset of T cells of patients with JRA may have an enhanced capacity for adhesion to endothelium.
8852515 Therapeutic effects of antibodies against adhesion molecules in murine collagen type II-in 1995 Adhesion molecules play important roles in immune reactions and inflammatory processes and may constitute attractive targets for immunomodulatory approaches. In this study, blocking mAbs against a series of adhesion molecules were tested for their therapeutic effect on developing arthritis in a mouse model. MAbs were given for a period of 4 weeks at the time of exspected incidence of visible disease symptoms, i.e. 4 weeks after priming with collagen type II. A significant reduction of incidence down to values of 13% and 29% of the controls was obtained with mAbs against CD44 and alpha 4-integrin, respectively, during an observation time of 13 weeks. MAbs against CD4 and LFA-1 resulted only in weaker, non-significant effects or a delay in the incidence. MAbs against other molecules including L-selectin, ICAM-1 or VCAM-1 were not effective. The development of antibodies against collagen type II, collagen type I, proteoglycans and the immunogen, bovine collagen type II was affected by mAb treatment to a different extent. In this case, the anti CD4 mAb was the most effective, followed by the anti alpha 4-antibodies in most cases, whereas anti CD44 showed less clear effects on the development of humoral responses. In a skin delayed type hypersensitivity model analyzed for comparison, mAbs against LFA-1/ICAM-1 and alpha 4-integrin showed the largest effects on ear swelling. These data show that mAbs against several adhesion molecules are able to block selectively distinct aspects of immune reactions, and that CD44 and alpha 4-integrins could be promising targets for an immunotherapy of rheumatoid arthritis with receptor-interfering agents.
7518753 Suppression of collagen-induced arthritis using an angiogenesis inhibitor, AGM-1470, and a 1994 Aug Collagen-induced arthritis (CIA) is a T-cell-dependent rat model of rheumatoid arthritis (RA) that is induced by injection of collagen type II in incomplete Freund's adjuvant. Neovascularization within the synovium is a prominent feature of CIA and RA. The novel angiogenesis inhibitor AGM-1470 and the microtubule-stabilizing agent Taxol represent two new classes of agents with specific mechanisms of action. AGM-1470 inhibits fibroblast growth factor-induced stimulation of endothelial cell migration, endothelial cell proliferation, and capillary tube formation, resulting in effective suppression of new blood vessel formation. By enhancing microtubule polymerization, Taxol interferes with normal microtubule function in cell mitosis, migration, chemotaxis, and intracellular transport. Using a suppression protocol in established CIA, the effects of AGM-1470 and Taxol as single agents and in combination were evaluated. Combination therapy significantly reduced clinical arthritis compared to control rats (P < 0.00001). The combination therapy group also experienced earlier and significantly greater reduction of clinical arthritis compared to either single agent-treated groups (P < 0.05). Blinded radiographic scores at the end of the study demonstrated less soft tissue swelling and joint destruction using combination therapy than either single agent. This is the first use of AGM-1470 and Taxol in combination therapy. Further study of agents with distinct mechanisms of action may lead to more effective treatment options in chronic inflammatory arthritis and to a better understanding of the pathophysiologic processes of pannus formation.
8628980 Toward an understanding of NSAID-related adverse events: the contribution of longitudinal 1996 The ARAMIS (Arthritis, Rheumatism and Ageing Medical Information System) databanks have been used to objectify and quantify drug toxicity. The relative risk of a gastrointestinal (GI)-provoked hospitalization was more than five times greater in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) than in non-NSAID-treated patients, with an excess hospitalization rate of 1.3% per annum. Additionally, there was an excess GI-related death rate of around 3% in rheumatoid arthritis (RA) patients compared with the normal population. Age, previous NSAID-related GI events, prednisone use, higher doses and greater disability predicted high-risk patients. A toxicity index showed clear differences between NSAIDs, with aspirin, salsalate and ibuprofen emerging as the least toxic, and meclofenamate and indomethacin as the most toxic. Disease modifying anti-rheumatic drugs (DMARDs) were, surprisingly, found to have similar toxicity scores to the NSAIDs. This supports the contemporary practice of employing DMARDs earlier and more aggressively in the course of RA.
8203952 Effect of three animal models of inflammation on nerve fibres in the synovium. 1994 Apr OBJECTIVES: Both sensory and sympathetic nerve fibres are depleted in the synovium in rheumatoid arthritis (RA). The hypothesis that the induction of an inflammatory response in the synovium is capable of causing depletion of nerve fibres was tested. METHODS: To investigate this phenomenon experimental arthritis in the rat was induced by three different methods and the synovium was examined for evidence of nerve depletion by immunocytochemistry. RESULTS: In a synovitis induced by latex spheres, a mainly macrophage foreign body type reaction, no nerve depletion was seen. In contrast both in an antigen-induced and a hydrogen peroxide-induced model of arthritis nerve fibre depletion was observed. This appeared to affect sensory and sympathetic nerve fibres equally. Nerve fibre depletion was only seen in areas of inflammatory cell infiltration indicating that a mixed lymphocyte and macrophage population of cells may be necessary for this effect. CONCLUSIONS: An inflammatory response, containing lymphocytes and macrophages, in the synovium is capable of the depletion of the finely myelinated and unmyelinated neuropeptide-containing nerves.
1466299 Metabolism and characterisation of kinins and Hoe 140 (kinin antagonist) in the synovial f 1992 Methods have been optimised for the collection of synovial fluid and the chromatographic separation of individual kinins (bradykinin and kallidin) in the fluid by HPLC. In addition, the stability of the kinin antagonist, Hoe 140, in synovial fluid was compared with that of synthetic bradykinin. Although bradykinin was completely degraded after incubation for only 6 h in pooled synovial fluid obtained from patients with rheumatoid arthritis, Hoe 140 was stable for as long as 2 weeks under the same conditions. These studies will provide quantitative information regarding levels of kinins in inflamed joints and an insight into the therapeutic potential of kinin antagonists.
8757015 Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's dise 1996 Aug Alzheimer's disease (AD) lesions are characterized by the presence of numerous inflammatory proteins. This has led to the hypothesis that brain inflammation is a cause of neuronal injury in AD and that anti-inflammatory drugs may act as protective agents. Seventeen epidemiologic studies from nine different countries have now been published in which arthritis, a major indication for the use of anti-inflammatory drugs, or anti-inflammatory drugs themselves have been considered as risk factors for AD. Both factors appear to be associated with a reduced prevalence of AD. The small size of most studies has limited their individual statistical significance, but similarities in design have made it possible to evaluate combined results. We have used established methods of statistical meta-analysis to estimate the overall chance of individuals exposed to arthritis or anti-inflammatory drugs developing AD as compared with the general population. Seven case-control studies with arthritis as the risk factor yielded an overall odds ratio of 0.556 (p < 0.0001), while four case-control studies with steroids yielded odds ratios of 0.656 (p = 0.049) and three case-control studies with nonsteroidal anti-inflammatory drugs (NSAIDs) yielded an odds ratio of 0.496 (p = 0.0002). When NSAIDs and steroids were combined into a single category of anti-inflammatory drugs, the odds ratio was 0.556 (p < 0.0001). Population-based studies were less similar in design than case-control studies, complicating the process of applying statistical meta-analytical techniques. Nevertheless, population-based studies with rheumatoid arthritis and NSAID use as risk factors strongly supported the results of case-control studies. These data suggest anti-inflammatory drugs may have a protective effect against AD. Controlled clinical trials will be necessary to test this possibility.
8371167 Demonstration of novel anti-arthritic and anti-inflammatory effects of diphosphonates. 1993 Sep Diphosphonates (DP) are synthetic pyrophosphates with a P-C-P backbone and are predominantly used for the treatment of bone diseases. Several DP have also been shown to exert significant antiarthritic effects in the rat adjuvant-induced polyarthritis model; however, there is no direct evidence for the anti-inflammatory effects of these compounds. We therefore tested the effects of dichloromethylene diphosphonate on delayed-type hypersensitivity granuloma elicited by s.c. implantation of antigen-soaked hydroxyapatite disks in antigen-sensitized mice. Dichloromethylene diphosphonate induced a dose-related inhibition of the delayed-type hypersensitivity granuloma response (38-64% at 25-100 mg/kg/day s.c. or p.o.); novel DP analogs, U-81581, U-82579 and U-84849 were also effective in the same dose range. In contrast, all DP failed to suppress 24-hr delayed-type hypersensitivity paw edema in mice. In addition to rat adjuvant-induced polyarthritis, mouse antigen-induced erosive arthritis was also significantly suppressed by s.c. administration of all four DP. Toxicity was minimal for each DP (> 600 mg/kg p.o. or s.c.). We conclude that DP represent a novel class of anti-inflammatory agents with excellent therapeutic potential for chronic inflammatory diseases including rheumatoid arthritis.
7855522 [Chronic juvenile arthritis]. 1994 Dec 1 Juvenile chronic arthritis encompasses a heterogeneous spectrum of diseases that all include at least one persistent inflammatory arthritis. Its definition is based upon clinical criteria after exclusion of a long list of differential diagnoses. Three main types of onset are generally considered according to the clinical features during the first 3 months of evolution: systemic (20%), oligoarticular (50%), polyarticular (30%). Systemic forms present with acute general symptoms and a wide variety of articular features, from polyarthritis to isolated arthralgias. Oligoarticular forms involve 4 or fewer joints and are often complicated with iridocyclitis especially in case of positive antinuclear antibodies in the serum. Polyarticular forms involve at least 5 joints and include the presence of rheumatoid factor in the serum in 10% of cases. The clinical course of juvenile chronic arthritis is unpredictable and the reliability of the current classification is limited by taking into account only the first 3 months of evolution.