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ID PMID Title PublicationDate abstract
14506365 New perspectives and emerging therapies for immune-mediated inflammatory disorders. 2003 Sep Chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and Crohn's disease, affect a large segment of the population in the United States. Recent research suggests that, in many inflammatory conditions, an inflammatory protein or cytokine, specifically tumor necrosis factor-alpha (TNF-alpha), appears to play an important role. Medications designed to treat these chronic inflammatory diseases, in addition to alleviating its symptoms, have become important therapeutic alternatives. This article will discuss specific Immune Mediated Inflammatory Disorders (I.M.I.D.), their treatment and management, as well as the current clinical application and potential future role of TNF-alpha antagonists as a common therapeutic modality.
12379638 Role of interleukin 15 and interleukin 18 in inflammatory response. 2002 Nov Interleukin 15 (IL15) and interleukin 18 (IL18) are cytokines produced principally by macrophages during innate immune response and subsequently profoundly influence adaptive immunity. Recent studies have shown that IL15 and IL18 play an influential part in inflammatory response. Here we present recent data mainly from our own laboratories illustrating the importance of IL15 and IL18 in the induction and perpetuation of chronic inflammation during experimental and clinical rheumatoid synovitis.
11852593 [Reliability and validition of the Slovak modified version of the Stanford Health Assessme 2002 Jan BACKGROUND: Functional disability is one of the most important consequences of RA in the patient's daily life. The HAQ has been widely used in its self administered form for the assessment of disability. A sensitive and valid instrument is needed for a Slovak population with RA. OBJECTIVE: To evaluate reliability and validity of the Slovak version of the HAQ in patients with RA and to explore relationships between HAQ score and disease activity and to provide information concerning utilization of this instrument in clinical practice. METHODS: In preparing the Slovak version of the HAQ careful attention has been paid to the translation, in terms of linguistic and conceptual equivalence, in order to preserve the original purpose of the instrument. The wording of some items required adaptation to the current activities of daily living and Slovak lifestyle. The sample consisted of 160 RA-patients, out of which 135 were women and 25 were men. The inclusion criteria were the following: age from 20 to 70 years at the onset of the study, diagnosis of RA according to the ARA criteria. The exclusion criteria were the presence of another serious disease or very disabling RA (stage IV of the Steinbrocker's classification). To analyze the data t-test, correlations, one-way analysis of variance (ANOVA), and principal component analysis (PCA) available in the SPSS/PC+ statistical package were used. RESULTS: The Cronbach's coefficient of reliability alpha for the HAQ total scale was 0.94. The results of PCA showed that the 20 HAQ items loaded on four components for which the eigen values were greater than 1, accounting for 70% of overall interpersonal variability. Orthogonal varimax rotation of the principal components provided factor loadings reflecting the eight dimensions within the HAQ. Validity of the HAQ was examined further by means of known-groups technique. The HAQ was found to be sensitive to differentiate between the Steinbrocker's functional capacity groups, as well as between males and females. Moreover, significant correlations (p < or = 0.01) were found between the HAQ and the C-reactive protein, the ESR, the NHP-pain, the Ritchie articular index, the Steinbrocker's functional capacity (r = 0.31-0.62) and disease duration (p < or = 0.05, r = 0.17). CONCLUSION: The results of the current investigation provide support for reliability and construct validity of the Slovak version of the HAQ in patients with RA. The HAQ has sufficient discriminant ability. The index disability can be used as an criterion of severity of RA, as a criterion of effectiveness in therapeutical trials for patient stratification of the Slovak population with RA.
14653204 [New diagnostic tests for rheumatoid arthritis]. 2003 Oct Rheumatoid factor(RF) is one item in the classification criteria for rheumatoid arthritis(RA), with a tolerable sensitivity of 69.3% for RA but low specificity against other rheumatic diseases(76.4%). Anti-agalactosyl IgG antibody(CARF) showed a slightly higher sensitivity(72.0%) but the specificity was even lower(67.9%). Anti-cyclic citrullinated peptide antibody(anti-CCP), a new diagnostic test for RA, demonstrated higher sensitivity(76.0%) and specificity(91.5%), and the ROC analysis revealed the marked superiority of anti-CCP to other markers(i.e. RF, CARF, and IgG-RF). Matrix metalloproteinase-3 (MMP-3) showed a significantly positive correlation with CRP, suggesting it might be more useful for evaluation of RA activity and prediction of the prognosis of joint destruction. On the contrary, two combination assays, "MMP-3 or CARF" and "MMP-3 or anti-CCP", showed the highest sensitivity(86.7%) for RA. Similarly, in early RA the sensitivities of CARF, MMP-3 and anti-CCP were lower than in RA(66.7%, 66.7% and 58.3%, respectively), but the sensitivities of combination assays "MMP-3 or CARF" and "MMP-3 or anti-CCP" were 91.7% and 83.3%, respectively. Thus, we concluded that these combination assays are useful in the diagnosis of RA and detection of early RA.
14707462 Immunomodulation by polyunsaturated fatty acids: mechanisms and effects. 2003 Dec Polyunsaturated fatty acids (PUFAs) modulate immune responses, thereby exerting beneficial effects in a variety of inflammatory disorders. PUFAs of the n-3 series that are found in marine fish oils are particularly effective. A variety of molecular mechanisms have been found to explain how PUFAs could interfere with immune cell function. PUFAs alter eicosanoid (prostaglandin, leukotriene) synthesis, orphan nuclear receptor activation (e.g. peroxisome proliferator-activated receptors, liver X receptors) and T lymphocyte signaling by changing the molecular composition of special signaling platforms called lipid rafts. This review discusses these mechanisms in detail with respect to their probable relevance in vivo. In addition, the effects of PUFAs on the immune system in general are summarized, as are clinical effects in rheumatoid arthritis, inflammatory bowel disease and sepsis.
15292811 Malignant fibrous histiocytoma at the site of a total hip arthroplasty. 2004 Aug Malignant fibrous histiocytoma is the most frequent sarcoma in adults. Predisposing factors for malignant fibrous histiocytoma are Paget's disease, bone infarcts, malignant disorders of the hematopoetic system, or prolonged intake of corticosteroids. Malignant fibrous histiocytoma has been described as occurring with increasing frequency after endoprosthetic therapy and has been attributed to the implants or to their alloy constituents. Malignant fibrous histiocytoma at the site of an endoprosthesis of the hip constitutes a distinct rarity. To our knowledge, only 13 cases have been described to date. In this report, we present the case of a 66-year-old woman with rheumatoid joint disease. Eight years after primary endoprosthetic surgery, loosening of the implant with severe osteolysis of the surrounding bone required replacement surgery. Histopathologic evaluation of resected tissue revealed scar and granulation tissue and Grade 3 malignant fibrous histiocytoma. The patient died 1 year after revision arthroplasty because of diffuse pulmonary and cerebral metastases. In patients with loosening of a total hip endoprosthesis in combination with severe periprosthetic osteolysis an accompanying malignancy should be in the differential diagnosis. The histopathologic examination of the resected tissue should be obligatory.
12767874 Evaluation of respiratory status and mandibular movement after total temporomandibular joi 2003 Jun We performed total TMJ replacement to improve respiratory status and correct occlusion in six patients with destruction of the temporomandibular joint (TMJ) caused by rheumatoid arthritis. Morphological changes were evaluated on lateral cephalograms before and after surgery. Respiratory function and mandibular movement were assessed with the use of an apnea-monitor and an LED mandibular tracking device, respectively. After surgery, symptoms such as snoring and daytime sleepiness improved, and solid food could be masticated. Postoperative cephalograms showed that both the posterior airway space and ramal height were significantly improved by surgery. Postoperative records of mandibular movement indicated stability of the occlusion and improvement of mandibular movement, as compared with the preoperative records. Mean oxygen saturation significantly improved 1 month after surgery, whereas apnea and apnea-hypopnea indices did not change significantly.
15541037 Platelet-derived growth factor-AA increases IL-1beta and IL-8 expression and activates NF- 2004 Nov The effect of platelet-derived growth factor (PDGF)-AA on the inflammation in rheumatoid arthritis (RA) and osteoarthritis (OA) was investigated using cultured fibroblast-like synoviocytes (FLS) obtained from RA and OA patients as well as control nonarthritic (NA) individuals. PDGF-AA increased the mRNA and protein expressions of proinflammatory cytokines, interleukin (IL)-1beta and IL-8 in RA FLS. Biological activity of IL-1 in the culture supernatant of RA FLS was also increased by PDGF-AA stimulation. Interestingly, PDGF-AA synergized with tumour necrosis factor (TNF)-alpha to upregulate the protein expressions of IL-1beta and IL-8. PDGF-induced enhancement of the IL-1beta and IL-8 mRNA expressions was also observed in OA FLS. However, the expression of these proinflammatory cytokines in NA FLS did not change by PDGF treatment, suggesting that the inflammatory condition might have modified the biological effects of PDGF. In accordance with the enhanced expression of inflammatory cytokines, the activity of nuclear factor kappaB was also induced in response to PDGF-AA in RA FLS. These results suggest that PDGF-AA plays an important role in the progression of RA inflammation, and inhibiting PDGF activity may be useful for the effective RA treatment.
15229945 Rate of change in functional limitations for patients with rheumatoid arthritis: effects o 2004 Jul OBJECTIVE: To estimate the rate of change in functional limitations for patients with rheumatoid arthritis (RA) as a function of age, duration of illness, and sex. METHODS: Patients with RA (n = 700) aged 21-65 years in 1988 were interviewed yearly for 6 years in The National Rheumatoid Arthritis Study. Functional limitations scores based on a Rasch measurement model of 20 Health Assessment Questionnaire items were analyzed in mixed-effects models to estimate the rate of change in functional ability as a function of age, duration of illness, sex, and interactions. RESULTS: Models for both patient age and duration of illness significantly predicted limitations in functional ability for men and women. The model for age included a significant cubic effect; the model for duration of illness included a significant linear effect only. Sex was significant in both models and no interactions were significant in either model. The AIC index of fit, an indicator of the information value of the model, favored the model for duration of illness over the model for age. While both models showed higher levels of functional limitations in women than men, the rate of change for women was similar to men. CONCLUSION: Limitation in functional ability in RA progressed in a linear manner with duration of illness and progressed at the same rate for both men and women, but functional limitations were greater for women.
12376082 An etiologic model proposing that non-insulin-dependent diabetes mellitus is chronic hypox 2002 Nov This etiologic model equates non-insulin-dependent diabetes mellitus (NIDDM) to chronic hypoxic stress hyperglycemia produced by increased stimulation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. In the initial stages of the disease, hypoxia is believed to result from hemodilutional anemia precipitated by a reduction in vascular smooth muscle tone. The reduction increases lumen diameter necessitating an increased blood volume to maintain pressure. Increased lumen diameter may also trigger atherosclerotic changes that characterize the later stages of NIDDM. The increased diameter decreases the shear stress experienced by endothelial cells and they respond by releasing endothelin, a smooth muscle constrictor and mitogen. The constricting action is hypothesized to be relatively ineffective in NIDDM leading to long-term endothelin release and activation of its mitogenic properties. The resulting increase in the number of smooth muscle cells may explain the intimal thickening of atherosclerosis. Restoration of vascular muscle tone is proposed as a treatment strategy for mild NIDDM.
14677177 Changes in 3D joint kinematics support the continuous use of orthoses in the management of 2003 Nov OBJECTIVE: To evaluate the efficacy of custom foot orthoses for the management of painful rearfoot valgus in patients with rheumatoid arthritis (RA). METHODS: Patients were randomized to receive custom-manufactured rigid carbon graphite foot orthoses (RA-orthosis) or enter a control group (RA-control) receiving no orthotic intervention. Three-dimensional (3D) kinematics were measured at the ankle joint complex (AJC) using an electromagnetic tracking (EMT) system under barefoot, shod, and orthosis walking conditions. Previously established normal 3D kinematic data were used to descriptively compare motion patterns in both RA groups and statistical analyses were performed on integrals of motion-time for each axis of rotation from data collected at baseline, 3, 6, 12, 18, 24, and 30 months. RESULTS: Compared with healthy control subjects, all patients with RA demonstrated excessive subtalar joint eversion motion through the stance phase of gait (p < 0.0001) coupled with excessive internal leg rotation (p < 0.0001). Custom-manufactured orthoses significantly reduced eversion through stance (p = 0.009) and re-established equilibrium of motion relative to neutral joint position. Correcting the frontal plane component of the deformity did not lead to a significant reduction in internal leg rotation (p = 0.294). The devices had no effect on tibiotalar dorsiflexion/plantarflexion (p = 0.960). Prospectively, the rigid orthoses maintained and then improved the reduction in cumulative subtalar eversion motion (p < 0.0001). Minimal changes in cumulative subtalar component eversion and internal leg rotation were recorded for both RA groups when walking barefoot but the effect was significantly less for the RA-control group. From 12 months onwards, internal leg rotation started to decrease, suggesting re-coupling of motion, but the overall motion pattern remained abnormal in comparison with normal reference values. CONCLUSION: These results support the continuous use of custom-manufactured foot orthoses to correct deformity and optimize AJC function in RA patients with early painful deformity of the rearfoot.
12610797 Tumor necrosis factor receptor 2 microsatellite and exon 6 polymorphisms in rheumatoid art 2003 Mar OBJECTIVE: To investigate the role of tumor necrosis factor receptor 2 microsatellite allele (TNFR2ms) and TNFR2 exon 6 polymorphisms in the pathogenesis of rheumatoid arthritis (RA) in Taiwan. Methods. TNFR2ms was determined in 114 patients with RA and 75 healthy controls by polymerase chain reaction (PCR) method and electrophoresis with sequencing gel. The TNFR2 exon 6 polymorphisms were also simultaneously measured by PCR restriction fragment length polymorphism method. RESULTS: The phenotypic and allelic frequencies of TNFR2ms 18 were significantly lower in patients with RA than in controls. The genotype frequency of TNFR2ms 16/18 was also significantly decreased in patients. In contrast, the phenotypic and allelic frequencies of TNFR2ms 15 showed a trend to be increased in patients with RA. There were no significant differences in the frequencies of various TNFR2ms and exon 6 polymorphisms concerning presence and absence of rheumatoid factor, bone erosion, rheumatoid nodules, or Sjögren's syndrome manifestation. Conclusion. TNFR2ms 18 may have a protective effect on the development of RA in Taiwanese, while TNFR2ms 15 tends to have a precipitating effect. TNFR2 exon 6 polymorphisms are not related to susceptibility for RA. TNFR2ms and exon 6 polymorphisms were not associated with the clinical manifestations of RA in Taiwanese. A synergistic effect for susceptibility to RA was found between TNFR2ms 15 and HLA-DR4.
12180492 Immunological effects and safe administration of alemtuzumab (MabCampath) in advanced B-cL 2002 Alemtuzumab (MabCampath) can purge both B- and T-cells in a variety of clinical situations, as seen in the treatment of autoimmune disorders and of lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL). One of the characteristics of advanced B-CLL is an increased susceptibility to infection, which may improve in patients whose disease responds to alemtuzumab, particularly when immune reconstitution by non-malignant stem cells is successful. However, at initiation of treatment, patients with advanced disease are likely to have poor immune function, and need careful management during and after treatment. Here, we present results showing the nature of immune reconstitution after alemtuzumab and the ways in which alemtuzumab may affect white cell counts during and after treatment. The management of B-CLL patients is discussed both in the context of minimizing acute "first-dose" events and with reference to the health risks already existing in this patient population. With protocols in place for dose escalation, for dose postponement in the event of cytopenia, and for anti-infective prophylaxis, alemtuzumab can be used effectively and safely in high-risk B-CLL patients.
15478162 Identification of modifiable work-related factors that influence the risk of work disabili 2004 Oct 15 OBJECTIVE: To define work-related factors associated with increased risk of work disability (WD) in people with rheumatoid arthritis (RA). METHODS: Questionnaires were mailed to all RA patients who used a province-wide arthritis treatment program between 1991 and 1998 (n = 1,824). The association between risk factors and WD (defined as no paid work due to RA for at least 6 months) was assessed using multiple logistic regression analysis, controlling for significant sociodemographic and disease-related variables. RESULTS: Of the original 1,824 patients, 581 were eligible and responded to the questionnaire. Work survival analysis revealed a steady rate of WD starting early, with 7.5%, 18%, and 27% work disabled at 1, 5, and 10 years, respectively. Significant determinants in multiple logistic regression were physical function (Health Assessment Questionnaire), pain (visual analog scale), and 6 work-related factors: self employment, workstation modification, work importance, family support toward employment, commuting difficulty, and comfort telling coworkers about RA. CONCLUSION: Work disability occurs early in RA. Novel work-related factors were identified, which are potentially modifiable, to help RA patients stay employed.
12220545 Cytokines and anti-cytokine biologicals in autoimmunity: present and future. 2002 Aug The increasing understanding of the role of cytokines in autoimmunity, and the observation that tumour necrosis factor alpha (TNFalpha) is central to the inflammatory and destructive process common to several human autoimmune diseases, has led to a new generation of therapeutics, the TNFalpha blocking agents. In this article, we review the current knowledge of the role of cytokines in autoimmunity as unravelled by studies both in the laboratory and the clinic. In addition, we discuss future prospects of the anti-TNFalpha therapy that may involve combination therapy with other anti-cytokine or anti-T cell biologicals, or the use of small chemicals targeting molecules involved in TNFalpha production such as NF-kappaB and p38 MAPK. The future developments of anti-TNFalpha and anti-cytokine therapy in general will be interesting.
15110230 P-glycoprotein in autoimmune diseases. 2004 Mar Multidrug resistance-1 (MDR-1) is characterized by overfunction of P-glycoprotein (P-gp), a pump molecule that decreases intracellular drug concentration by effluxing them from the intracellular space. Broad ranges of structurally unrelated compounds are transported by P-gp, including antineoplastic agents, HIV protease inhibitors, prednisone, gold salts, methotrexate, colchicine as well as several antibiotics. In contrast, many other compounds such as calcium channel blockers (verapamil) and immunosupressors (cyclosporine-A) are able to inhibit P-gp function. The P-gp role in therapeutic failures has been extensively studied in cancer; however, there is little information regarding MDR-1 phenotype in autoimmune disorders. It has been reported that an increased number of lymphocytes are able to extrude P-gp substrates in rheumatoid arthritis, immune thrombocytopenic purpura and systemic lupus erythematosus, the patients with poor response to treatment being the ones that exhibit the highest values. This may be due, at least in part, to a simultaneous long-term usage of several drugs that induce P-gp function. Since abnormally activated cell compartments characterize autoimmune diseases, it is possible that those cells are the ones that exhibit drug resistance. The study of drug resistance mechanisms in autoimmunity may be helpful for the optimization of the current therapeutic schemes through their combination with low doses of P-gp inhibitors.
12935777 Dissection of the genetic complexity of arthritis using animal models. 2003 Sep The exploding progress in genomic technology and knowledge now opens the possibility to actually identify the molecular mechanisms in disease. However, inflammatory diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS), are complex and polygenic and remain a challenge. One possible shortcut could be the use of inbred animals as models for RA and MS for the genetic analysis. These models have been extensively characterized and show a similar degree of complexity as the corresponding human diseases. Using these models linkage analysis followed by isolation of the loci in congenic strains have been shown to be highly efficient and have provided fundamental new knowledge on the genetic control of these diseases. The genetically controlled congenic strains are also useful as scientific tools. They can be used for the identification of the disease-associated genes and, thereby, the essential disease pathways that have been selected by nature. We know that this is possible since we have succeeded in identifying the genes within two of the congenic regions; the MHC class II gene Aq controlling immune response and the Ncf1 gene controlling oxidative burst. Both of these genes are associated with T cell activation and arthritis severity.
12379627 Infliximab treatment for rheumatic disease: clinical and radiological efficacy. 2002 Nov Infliximab is a chimeric anti-tumour necrosis factor alpha (TNFalpha) monoclonal antibody with high affinity and binding specificity for human TNFalpha. Results from several well designed, controlled clinical trials show repeated infusions of infliximab with concomitant methotrexate (MTX) treatment can reduce the signs and symptoms of rheumatoid arthritis (RA). This combination of infliximab and MTX also slows the radiological progression of joint damage, decreases functional disability, and improves qualify of life. These remarkably positive results have led to the investigation of infliximab treatment for other rheumatic diseases. Recently, controlled studies have shown treatment with infliximab can benefit patients with active spondyloarthropathy. TNFalpha has fast become an important therapeutic target in rheumatology.
14983105 How aggressive should initial therapy for rheumatoid arthritis be? Factors associated with 2004 May OBJECTIVE: To determine what baseline factors might be associated with response to an initial mild treatment regimen in patients with early rheumatoid arthritis (RA). METHODS: Open label 2-yr study of 111 consecutive patients with early RA of duration less than 1 yr. None of the patients had previously received disease-modifying anti-rheumatic drugs (DMARDs). All patients were assigned to receive hydroxychloroquine (HCQ) at enrollment, and could also take non-steroidal anti-inflammatory drugs (NSAIDs) and prednisone. At any point during follow-up, patients not fulfilling the American College of Rheumatology (ACR) 50 criteria for improvement and/or who were taking prednisone > 10 mg/day were considered treatment failures and therapy changed to methotrexate (MTX), 7.5-20 mg/week. Clinical, laboratory and immunogenetic factors potentially predictive of treatment assignment at month 24 were evaluated. RESULTS: After 24 months of follow-up, a majority of patients (56/94) were either still on solo DMARD therapy with HCQ (n = 49) or off DMARD therapy with controlled/quiescent disease (n = 4), and 38 patients were taking MTX (including 11 in combination with other DMARDs). At month 24, all but 9 patients met ACR50 criteria for treatment response. Features present at enrollment which were predictors of MTX therapy at month 24 were high pain score, baseline rheumatoid factor titre > 1:40, higher number of swollen joints, and poor patient global assessment. The presence of HLA-C7xx at enrollment was also predictive of need for MTX therapy. CONCLUSIONS: This study suggests that even milder treatment with HCQ is greatly beneficial in patients with early RA. There continue to be very few consistently reliable predictors of treatment needs in patients with this disease.
14607962 Direct inhibition of NF-kappa B blocks bone erosion associated with inflammatory arthritis 2003 Nov 15 Inflammatory arthritis is associated with devastating joint tissue destruction and periarticular bone erosion. Although secreted products of infiltrating immune cells perpetuate the inflammatory response, the osteolytic component of this disease is a direct result of localized recruitment and activation of osteoclasts. Given that NF-kappaB plays a central role in both processes, the function of this transcription factor was examined. Using a mouse model of autoreactive Ig transfer that engenders inflammatory arthritis, we show numerous osteoclasts in the articular joint tissue associated with progressive periarticular osteolytic lesions. Moreover, cells retrieved from these joints exhibit heightened NF-kappaB activity. Importantly, direct administration of dominant negative*I-kappaB or tyrosine 42-mutated I-kappaB (Y42F*I-kappaB) proteins into mice before induction of the disease attenuates in vivo activation of the transcription factor. More importantly, these I-kappaB mutant forms significantly inhibit in vivo production of TNF and receptor activator of NF-kappaB ligand, and block joint swelling, osteoclast recruitment, and osteolysis. Thus, NF-kappaB appears to be the centerpiece of inflammatory-osteolytic arthritis and direct inhibition of this transcription factor by unique and novel I-kappaB mutant proteins blocks manifestation of the disease.