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ID PMID Title PublicationDate abstract
12904288 Nramp1-mediated innate resistance to intraphagosomal pathogens is regulated by IRF-8, PU.1 2003 Nov 7 Natural resistance-associated macrophage protein 1 (Nramp1) is a proton/divalent cation antiporter exclusively expressed in monocyte/macrophage cells with a unique role in innate resistance to intraphagosomal pathogens. In humans, it is linked to several infectious diseases, including leprosy, pulmonary tuberculosis, visceral leishmaniasis, meningococcal meningitis, and human immunodeficiency virus as well as to autoimmune diseases such as rheumatoid arthritis and Crohn's disease. Here we demonstrate that the restricted expression of Nramp1 is mediated by the macrophage-specific transcription factor IRF-8. This factor exerts its activity via protein-protein interaction, which facilitates its binding to target DNA. Using yeast two-hybrid screen we identified Myc Interacting Zinc finger protein 1 (Miz-1) as new interacting partner. This interaction is restricted to immune cells and takes place on the promoter Nramp1 in association with PU.1, a transcription factor essential for myelopoiesis. Consistent with these data, IRF-8 knockout mice are sensitive to a repertoire of intracellular pathogens. Accordingly, IRF-8-/- mice express low levels of Nramp1 that can not be induced any further. Thus, our results explain in molecular terms the role of IRF-8 in conferring innate resistance to intracellular pathogens and point to its possible involvement in autoimmune diseases.
12559599 Monoclonal antibodies to human cartilage oligomeric matrix protein: epitope mapping and ch 2003 Feb BACKGROUND: Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP 5) is one of the most promising serologic markers with regard to an ability to prognose development of osteoarthritis (OA). Our aim was to map the epitopes of three monoclonal antibodies (mAb) to COMP and to develop and characterize a sandwich enzyme-linked immunosorbent assay (ELISA) for measuring COMP levels in human body fluids. METHODS: COMP was digested with trypsin and the NH(2)-terminal sequence of the fragments recognized by each of the mAbs was determined. Steric competition among the mAbs was tested with an antibody capture assay. A sandwich ELISA was developed using unlabeled mAb 16-F12 as a capture antibody, and mAb 17-C10 labeled with biotin as the second antibody. RESULTS: Epitopes of the three mAbs were mapped to three different domains within the COMP subunit (16-F12, NH(2)-terminal domain; 17-C10, EGF-like domain; 12-C4, COOH-terminal domain). These epitopes did not overlap. mAbs 17-C10 and 12-C4 yielded similar serum COMP results when used as the secondary antibodies. Serum COMP levels measured with the new sandwich ELISA using mAbs 16-F12 and 17-C10 correlated strongly with results based on an inhibition ELISA with mAb 17-C10 alone (r(2) = 0.836; P < 0.0001). We characterized the new sandwich ELISA with regards to inter- and intra-assay variability, the range of COMP levels that can be expected in human synovial fluids (SF) and sera (controls and OA and rheumatoid arthritis (RA) patients), and the day-to-day and diurnal variability of COMP levels in sera. CONCLUSIONS: We have developed and characterized a sandwich ELISA for COMP that is sensitive and yields highly reproducible COMP results upon analysis of human sera and synovial fluids.
12469182 Constitutive expression of cytotoxic proteases and down-regulation of protease inhibitors 2003 Jan Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder often associated with rheumatoid arthritis. The etiology of LGL leukemia is not known. In order to better understand the pathogenesis of LGL leukemia, we analyzed differential gene expression using microarray technology. We found that approximately 80 genes were up-regulated and 12 genes were down-regulated when compared to normal peripheral blood mononuclear cells (PBMC). In the present study, we were interested in a group of genes involved in cytotoxic function. The up-regulated genes involved in cytotoxic function were serine proteinases (granzymes A, B, H and K) cysteine proteinases [cathepsin C, cathepsin W (lymphopain)], calpain small subunit and caspase-8. In addition, a pore-forming protein perforin, was also up-regulated. Northern blot analysis and RNase protection assays (RPA) confirmed that these genes were over-expressed in the majority of samples from LGL leukemia patients. Of interest, proteolytic inhibitors such as cystatin C, A, alpha-1 antitrypsin and metalloproteinase inhibitors were down-regulated in leukemic LGL when compared to normal peripheral blood mononuclear cells. Importantly, the pattern of gene expression in leukemic LGL resembles that seen in activated cytotoxic T cells (CTL).
20641584 4-[(18)F]Fluorobenzoyl-ε-Lys(1)-c(KRGDe)MDDPGRNPHhCitGPAT. 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The peptide sequence Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3) and α(v)β(5). Various ligands have been introduced for imaging of tumors and tumor angiogenesis (8). Various radiolabeled cyclic RGD peptides and peptidominetics have been found to have high accumulation in tumors (9, 10). Both α(v)β(3) and α(v)β(5) integrins bind to vitronectin (11). However, whereas the α(v)β(3) integrin is required for basic fibroblast growth factor–mediated angiogenesis, the α(v)β(5) integrin is required for vascular endothelial growth factor–induced angiogenesis (12, 13). Therefore, there is a need for ligands capable of discriminating between α(v)β(3) and α(v)β(5). Del Gatto et al. (14) have developed a series of chimeric RGD echistatin C-terminal domain (RGDechi) antagonist peptides that showed a high selectivity for the α(v)β(3) integrin over the α(v)β(5) integrin. One of them, c(KRGDe)MDDPGRNPHhCitGPAT (RGDechi-hCit), retains binding to α(v)β(3) but fails to bind to α(v)β(5). Zannetti et al. (15) used N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB) to synthesize [(18)F]FB-RGDechi-hCit for tumor targeting.
12532108 There is no evidence of an inverse relationship between TH2-mediated atopy and TH1-mediate 2003 Jan BACKGROUND: The findings of an inverse relationship between T(H)1- and T(H)2-mediated disorders would provide strong empiric support to the hygiene hypothesis. OBJECTIVE: We sought to investigate the relationship between T(H)2-mediated atopic allergy and T(H)1-mediated autoimmune conditions in a nationally representative population. METHODS: We used logistic regression to analyze adult data from the Third National Health and Nutrition Examination Survey. Data on allergic and autoimmune disease history were available for 20,050 subjects, and data on atopy were available for a subsample of 7304 subjects. Atopy was defined by one or more positive skin prick test responses (wheal of > or =3 mm) to 10 common aeroallergens. Allergic disease was defined by patient reports of physician-diagnosed asthma, hay fever, or both. T(H)1-mediated autoimmune disease was defined by patient reports of physician-diagnosed type 1 diabetes mellitus, thyroid disorders, and/or rheumatoid arthritis. RESULTS: Adjusted for age and sex and taking into account the complex survey design, there was no relationship between atopy and a history of autoimmune disorders (adjusted odds ratio, 1.01; 95% CI, 0.61-1.67; P =.97). In contrast, physician diagnosis of allergic disorders was associated with a significant increased risk of physician-diagnosed autoimmune disorders (adjusted odds ratio, 1.67; 95% CI, 1.35-2.07; P <.001). CONCLUSION: We found no evidence of an inverse relationship between atopy and patient reports of physician-diagnosed common autoimmune disorders in the adult American population. Contrary to our initial hypothesis, reports of physician-diagnosed common allergic disorders are positively associated with reports of physician-diagnosed autoimmune disorders, with this possibly being caused by ascertainment bias. These findings suggest that the T(H)1/T(H)2 paradigm might be an oversimplification.
12508404 Detection of interleukin 1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in skin o 2003 Jan OBJECTIVE: To determine if abnormal collagen metabolism is correlated with neurogenic inflammation, a potential activator of collagen metabolism, in patients with fibromyalgia (FM). METHODS: The presence of inflammatory cytokines, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-a was investigated in skin tissues by using reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Fifty-three skin biopsies from female patients with FM (30-65 years of age) were examined and compared to skin biopsies of 10 age and sex matched healthy controls. Biopsies were obtained from the left deltoid region. Rheumatoid arthritis synovial fibroblasts and tissues were used as positive controls for the expression of cytokines. Total RNA isolated from the tissue samples were reverse transcribed (RT) by random hexamers as the primer for RT followed by PCR amplification using specific primers for IL-1beta, IL-6 or TNF-a. Expression of IL-1beta, and TNF-a protein was investigated in the skin by immunohistochemistry using specific antibodies (avidin-biotin method). RESULTS: Positive signals (RT-PCR) were detected in skin tissues of 19/50 (38%) FM patients for IL-1beta, in 14/51 FM patients (27%) for IL-6, and in 17/53 patients (32%) for TNF-a. None of the cytokines could be detected in healthy control skin. Immunoreactivity for IL-1beta and TNF-a was demonstrated in certain skin tissues of our FM patients. CONCLUSION: The detection of cytokines in FM skin indicates the presence of inflammatory foci (neurogenic inflammation) in the skin of certain patients (about 30% of FM patients), suggesting an inflammatory component in the induction of pain. This may explain the response to nonsteroidal antiinflammatory therapy in a subset of FM patients.
12466042 Tetrandrine and related bis-benzylisoquinoline alkaloids from medicinal herbs: cardiovascu 2002 Dec Tetrandrine (TET), a bis-benzylisoquinoline alkaloid purified and identified an active ingredient in a Chinese medicinal herb, radix stephanae tetrandrae, has been used traditionally for the treatment of congestive circulatory disorder and inflammatory diseases. TET, together with a few of its structural analogues, has long been demonstrated to have antihypertensive action in clinical as well as animal studies. Presumably, the primary anti-hypertensive action of TET is due to its vasodilatory properties. TET prevents or inhibits vascular contraction induced by membrane depolarization with KCl or alpha-adrenoceptor activation with phenylephrine (PE). TET (30 micromol/L) also inhibits the release of endothelium-derived nitric oxide (NO) as well as NO production by inducible NO synthase. TET apparently inhibits multiple Ca2+ entry pathways as demonstrated in cell types lacking the L-type Ca2+ channels. In cardiac muscle cells, TET inhibits both L- and T-type Ca2+ channels. In addition to its actions on cardiovascular tissues, TET may also exert its anti-hypertensive action via a Ca2+-dependent manner on other tissues intimately involved in the modulation of blood pressure control, such as adrenal glands. In adrenal glomerulosa cells, KCl- or angiotensin II-induced aldosterone synthesis is highly dependent on extracellular Ca2+. Steroidogenesis and Ca2+-influx in bovine adrenal glomerulosa cells have been shown to be potently inhibited by TET. In bovine adrenal chromaffin cells, TET inhibits Ca2+ currents via L- and N-type channels as well as other unidentified channels with IC50 of 10 micromol/L. Other than the Ca2+ antagonistic effects, TET also interacts with the alpha-adrenergic receptors and muscarinic receptors based on functional as well as radioligand binding studies. Apart from its functional effects, TET and related compounds also exert effects on tissue structures, such as remodelling of hypertrophied heart and inhibition of angiogenesis, probably by causing apoptotic responses. TET is also known for its anti-inflammatory and anti-fibrogenic actions, which make TET and related compound potentially useful in the treatment of lung silicosis, liver cirrhosis, and rheumatoid arthritis.
12390327 The level of IgA antibodies to human umbilical vein endothelial cells can be enhanced by T 2002 Nov Anti-endothelial cell antibodies (AECA) have been found to play an important role in many vascular disorders. In order to determine the presence of AECA in children with Henoch-Schönlein purpura (HSP), and to elucidate the pathogenic and clinical value of their measurement in this disease, AECA were detected by immunofluorescence staining and a human umbilical vein endothelial cell (HUVEC)-based enzyme-linked immunosorbent assay (ELISA) in 20 children with HSP, 10 children with juvenile rheumatoid arthritis (JRA) without vasculitis and 10 normal healthy children. Antibodies against another endothelial cells, human dermal microvascular endothelial cells (HMVEC-d) were also detected by cell-based ELISA. In some experiments, we compared the binding activity of antibodies to HUVEC with and without tumour necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1) pretreatment. Patients with acute onset of HSP had higher serum levels of IgA antibodies, both against HUVEC and against HMVEC-d, than healthy controls (P = 0.001, P = 0.008, respectively). Forty-five per cent of patients had positive IgA AECA to HUVEC, and 35% had positive IgA AECA to HMVEC-d. The titres of IgA antibodies to HUVEC paralleled the disease activity. After TNF-alpha treatment, the values of IgA AECA to HUVEC in HSP patients were significantly increased (P = 0.02). For IgG and IgM AECA, there was no difference between HSP patients and controls (P = 0.51, P = 0.91). Ten JRA children without vasculitis had no detectable IgG, IgM or IgA AECA activity. The results of this study showed that children with HSP had IgA AECA, which were enhanced by TNF-alpha treatment. Although the role of these antibodies is not clear, IgA AECA provide another immunological clue for the understanding of HSP.
12242468 Non-transmitted maternal HLA DQ2 or DQ8 alleles and risk of Type I diabetes in offspring: 2002 Sep AIMS/HYPOTHESIS: Type I (insulin-dependent) diabetes mellitus results from an immune-mediated destruction of pancreatic beta cells for which HLA haplotypes DR3-DQ2 and DR4-DQ8 represent the strongest genetic risk markers. Mothers of patients with rheumatoid arthritis carry more frequently the HLA DR4-DQ8 haplotype as non-transmitted haplotype than mothers of healthy control subjects. As maternal cells have been shown to persist in their offspring up to 30 years after birth, we investigated whether the association of HLA DR3-DQ2 and DR4-DQ8 with Type I diabetes is purely a genetic effect acting through inheritance or whether it can also act as an environmental factor, for example through foetal exposure in utero to maternal circulating cells. METHODS: We analysed the non-transmitted parental HLA DQ alleles of 464 families (1367 subjects) with a Type I diabetic offspring. HLA DQ alleles were assessed using sequence-specific primers and allele-specific oligonucleotides hybridisation. A chi-square test was done to compare allele and transmission frequencies in the respective subsets of families. RESULTS: The non-transmitted HLA DR3-DQ2 and DR4-DQ8 were more frequent in mothers than in fathers of all non- DQ2/DQ8 heterozygous diabetic offspring ( p=0.0001) as well as in offspring not carrying any HLA high-risk allele ( p=0.0243). In patients with either risk allele alone, more maternal than paternal non-transmitted risk alleles complemented the constellation to DQ2/DQ8 ( p<0.0099). CONCLUSION/INTERPRETATION: HLA high risk alleles were more frequent among maternal non-inherited (but possibly exposed) alleles than among paternal non-inherited alleles. These results indicate that HLA DR-DQ is an environmental risk factor for Type I diabetes.
12022359 Free HLA class I heavy chain-carrying monocytes--a potential role in the pathogenesis of s 2002 May OBJECTIVE: A fully complexed HLA-B27 molecule consists of a heavy chain, a peptide, and beta2-microglobulin (beta2m). The heavy chain can also exist free of beta2m. It has been proposed from animal and in vitro experiments that the free heavy chain is responsible for disease. We wanted to determine the following for patients with ankylosing spondylitis (AS): (1) are there cells expressing cell surface free heavy chains; (2) if so, which subset of cells has such capacity; (3) does expression vary with disease activity; (4) can we find free heavy chain-expressing cells at the site of inflammation that is characteristic of the disease; and (5) can such expression be induced in healthy subjects. METHODS: Quantitative flow cytometry was carried out using antibodies directed separately against HLA class I complex, free heavy chain A or B alleles. Antibodies directed against other cell surface markers were used to identify cell types. Immunohistochemical staining was used to stain synovial tissue. RESULTS: There was a high level of surface expression of free heavy chains in monocytes of patients with AS. The level exceeded those of normal controls and patients with rheumatoid arthritis. The level of expression correlated with the inflammation marker, erythrocyte sedimentation rate. The level of expression was enhanced when monocytes from healthy controls were driven to differentiation by longterm culture. Free heavy chain-expressing monocytes infiltrated the synovium of an involved hip joint of a patient with AS. CONCLUSION: This is the first patient-related evidence that surface free heavy chains of HLA-B27 have to be considered as potential disease-causing molecules.
15575004 Acute glomerulonephritis occurring during immunoadsorption with staphylococcal protein A c 2004 Dec BACKGROUND: Apheresis of patient plasma by immunoadsorption with a staphylococcal protein A (SPA) column is used in a variety of autoimmune disorders. Leukocytoclastic vasculitis is an uncommon severe complication that can occur during immunoadsorption with SPA (Prosorba. METHODS: We report a case of immune complex glomerulonephritis occurring during Prosorba immunoabsorption in a patient with rheumatoid arthritis (RA). Using a Medline literature search and information provided by Cypress Bioscience/Fresenius Hemocare, we review renal complications associated with Prosorba immunoadsorption. RESULTS: We identified seven additional potential cases of glomerulonephritis (GN) in association with Prosorba immunoadsorption. Five of these patients were being treated for RA, and two for idiopathic thrombocytopenia purpura (ITP). Renal biopsies were performed on four patients, all of whom had evidence of immune complex GN. Among RA patients treated with Prosorba, the incidence of GN closely paralleled that of leukocytoclastic vasculitis at 1.75%. The presence of leukocytoclastic vasculitis was a significant risk factor for the development of GN (relative risk = 75.95, CI 7-1869, P = 0.00021). In contrast, among more than 10 000 ITP patients treated with Prosorba, there were only two potential cases of GN. The risk of developing GN in association with Prosorba immunoadsorption was significantly greater for patients with RA than for those with ITP (relative risk = 62.95, CI 10-453, P = 0.00002). CONCLUSION: This case series highlights the risk of GN among patients undergoing SPA immunoadsorption. The development of GN is associated with the presence of leukocytoclastic vasculitis. Patients with RA seem to be at particular risk.
15454179 Parent-reported health status after pediatric thoracic organ transplant. 2004 Sep BACKGROUND: Thoracic organ transplantation is a life-changing event for a child and family from both a physical and a psychosocial perspective. Accurate pre-transplantation counseling and effective post-transplantation follow-up depend on a good understanding of post-transplantation health status, especially as perceived by families. METHODS: The Child Health Questionnaire-Parent Form 50 (CHQ-P50), an instrument that assesses parent-reported health status of pediatric patients, was administered to 47 pediatric thoracic organ transplant recipients (41 heart, 6 lung) 5 to 18 years of age. RESULTS: Transplant recipients scored lower on the Physical Health Summary (PhS) score than the general population, as evidenced by a lower median score (50.6 vs 55.1, p < 0.0001) and a difference in the distribution of quartiles (p = 0.001), skewed toward the lower quartiles of the general population. The distribution of PhS scores in transplant recipients was comparable to scores of 3 groups of pediatric patients with other chronic health conditions (juvenile rheumatoid arthritis, epilepsy and asthma). The distribution of the Psychosocial Health Summary (PsS) scores was similar to that of the general population, but the median score was lower (51.5 vs 53.2, p = 0.02). Transplant patients clearly scored lower than the general population on 4 of 12 sub-scales, including those assessing general health, physical functioning, family activities and parental emotional impact. No difference was found in sub-scales reflecting self-esteem, mental health, behavior, pain, peer interactions, family cohesion or parental time demands. CONCLUSIONS: Thoracic organ transplantation in children ages 5 to 18 years is associated with an ongoing deficit in parent-perceived physical health status.
15313405 Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular t 2004 Sep 15 Expression of cyclooxygenase-2 (COX-2) has been reported to be elevated in human colorectal adenocarcinoma and other tumors, including those of breast, cervical, prostate, and lung. Genetic knock-out or pharmacological inhibition of COX-2 has been shown to protect against experimentally-induced carcinogenesis. Results from epidemiological and laboratory studies indicate that regular intake of selective COX-2 inhibitors reduces the risk of several forms of human malignancies. Thus, it is conceivable that targeted inhibition of abnormally or improperly elevated COX-2 provides one of the most effective and promising strategies for cancer chemoprevention. The COX-2 promoter contains a TATA box and binding sites for several transcription factors including nuclear factor-kappaB (NF-kappaB), nuclear factor for interleukin-6/CCAAT enhancer-binding protein (NF-IL6/C/EBP) and cyclic AMP response element (CRE) binding protein. Upregulation of COX-2 is mediated by a variety of stimuli including tumor promoters, oncogenes, and growth factors. Stimulation of either protein kinase C (PKC) or Ras signaling enhances mitogen-activated protein kinase (MAPK) activity, which, in turn, activates transcription of cox-2. Celecoxib, the first US FDA approved selective COX-2 inhibitor, initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, has been reported to reduce the formation of polyps in patients with familial adenomatous polyposis. This COX-2 specific inhibitor also protects against experimentally-induced carcinogenesis, but the underlying molecular mechanisms are poorly understood. The present review covers the signal transduction pathways responsible for regulating COX-2 expression as novel molecular targets of chemopreventive agents with celecoxib as a specific example.
15151098 [Arthroscopy in the diagnosis and therapy of wrist disorders]. 2004 PURPOSE OF THE STUDY: Arthroscopy of the wrist is a method facilitating the establishment of diagnosis in patients with wrist complaints which may also serve for surgical management of some of the causes of wrist pathology. The author presents his first experience with carpal arthroscopy as a diagnostic method as well as a therapeutic technique performed in one or two stages. MATERIAL: A total of 34 patients, 12 women and 22 men, in the age range of 14 to 64 years, underwent carpal arthroscopy. This was performed to treat acute or chronic conditions in 16 and 18 patients, respectively. METHODS: Arthroscopy was carried out with the hand in vertical traction, using distraction forces of 50 to 70 N, from the approach between the third and fourth or/and the fourth and fifth extensor compartments, in order to inspect the mediocarpal joint by an arthroscope with a diameter of 2.4 mm. Neither a tourniquet nor a pump was employed. When a lesion was detected, it was treated by arthroscopy or an open procedure in one surgical procedure. When indicated, further surgical intervention followed. RESULTS: The arthroscopic inspection revealed triangular fibrocartilagenous complex (TFCC) lesions in 18 patients. Injury to the scaphoid-lunate (SL) ligament was found in 16 patients. One patient had a combined lesion of the triquetral-lunate and SL ligaments, two showed a SL lesion together with a distal radius fracture, three were diagnosed with pseudoarthrosis of the scaphoid bone and one with synovitis after rheumatoid arthritis. In two patients, adhesions in the radiocarpal joint following a fracture of the distal radius were found and shaved. A total of 22 patients were treated by arthroscopic surgery; 19 underwent open procedures in one stage and five were indicated for secondary surgery. DISCUSSION: Wrist arthroscopy has been reported in the literature as the only method that can reveal damage to SL ligaments not shown by X-ray or magnetic resonance imaging examination. During arthroscopy, several interventions can directly be carried out by this procedure, such as treatment of the TFCC, and thus relieve the patient's complaints. Arthroscopy is irreplaceable in the diagnosis of dynamic carpal instability or injury to TFCC in ulnar-carpal impingement. Our experience suggests that arthroscopically-guided osteosynthesis of the distal radius has great prospects. CONCLUSIONS: In our hospital acute arthroscopy is indicated when carpal connective tissue lesions, potentially leading to wrist instability, are suspected, when damage to carpal ligaments is found by X-ray examination or when an acute TFCC lesion is suspected. Arthroscopically-guided osteosynthesis of the distal radius appears to be a prospective method. In patients with chronic complaints, wrist arthroscopy is indicated in suspected TFCC lesions with ulnar-carpal impingement, in chronic carpal synovitis, and before sperious operations on the carpal bones in order to ascertain the state of cartilage and plan the appropriate surgery.
15061685 Safety of tumour necrosis factor-alpha antagonists. 2004 Tumour necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine that is synthesised by a variety of cell types in response to infectious or inflammatory stimuli. Although TNFalpha plays an adaptive role in immune protection and wound healing at 'physiological' levels, excess TNFalpha production can lead to adverse consequences. TNFalpha is a pivotal cytokine involved in the pathogenesis and progression of rheumatoid arthritis (RA). TNFalpha antagonists have been shown to be effective in the treatment of signs and symptoms of RA and the US FDA has approved three TNFalpha antagonists, etanercept, infliximab, and most recently, adalimumab, for the treatment of RA. However, differences have emerged, with respect to their demonstrated efficacy in other diseases (e.g. Crohn's disease). Worldwide, over half a million patients have been treated with TNFalpha antagonists and concerns regarding their safety have been raised. There is a risk of reactivation of granulomatous diseases, especially tuberculosis, with all three agents and appropriate measures should be taken for detection and treatment of latent infections. An association between non-Hodgkin's lymphoma and treatment with TNFalpha antagonists has been reported, although patients with active, long-standing RA are already known to have an increased incidence of non-Hodgkin's lymphoma. No associations with solid tumours have been found to date. The biological plausibility of lymphomas associated with immunomodulatory agents raises concern and vigilance is appropriate until the relationship is fully characterised. Large phase II and III trials have shown a detrimental effect of TNFalpha antagonists in advanced heart failure and these agents should be avoided in this population. Rare case reports of drug-induced lupus, seizure disorder, pancytopenia and demyelinating diseases have been noted after TNFalpha antagonists and continued vigilance is warranted in patients on TNFalpha antagonists for the development of these diseases. At present there is no evidence implicating TNFalpha antagonists with embryotoxicity, teratogenicity or increased pregnancy loss.
15046525 Costimulation blockade in the treatment of rheumatic diseases. 2004 The autoimmune response is executed via cognate interactions between effector immune cells and antigen presenting cells. Cognate interactions provide the immune effectors with specific signals generated through the antigen receptor as well as with second, non-specific signals, generated from the interaction of pairs of cell-surface molecules (costimulatory molecules) present on their plasma membrane. Disruption of this second, non-specific costimulatory signal results in the interruption of the productive (auto)immune response, leading to anergy, a state of immune unresponsiveness. The CD28:B7 families of molecules and the CD40:CD40L pair of molecules are considered as critical costimulatory elements. Disruption of the CD28:B7 interaction using a genetically engineered soluble form of the inhibitory molecule CTLA4 in vitro, as well as in experimental models of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), led to the inhibition of the autoimmune response. Similarly, promising data stem from the use of an anti-CD40L monoclonal antibody (mAb) in murine SLE. While such treatments prevent the development of autoimmunity in animal models, this preventive approach is inapplicable to human diseases. However, the rational bench-to-bedside approach led investigators to clinical trials of CTLA4-Ig and of two different humanized anti-human CD40L mAbs in patients with RA and SLE, respectively. Initial experience with the use of CTLA4-Ig in patients with RA is encouraging, since in one short-term trial the construct was well-tolerated and produced clinically meaningful improvement of the disease in a significant proportion of those treated. Surprisingly, the anti-CD40L mAb treatment approach in human lupus was not fruitful, since short-term administration of the anti-CD40L mAb ruplizumab in lupus nephritis was correlated with life-threatening prothrombotic activity despite initial encouraging data in the serology and renal function of the patients. Also, IDEC-131 anti-CD40L mAb treatment did not prove to be clinically effective in human SLE, despite being well tolerated. Precise tailoring of the administration schemes for these novel therapeutic modalities is awaited.Finally, conceptually different approaches to block costimulation by inhibiting the induced expression of costimulatory molecules or the transmission of their specific intracytoplasmic signal have already produced encouraging preliminary results.
15037212 Cetirizine and allopurinol as novel weapons against cellular autoimmune disorders. 2004 Mar Type 1, or cellular, immune response is characterized by overproduction of TNF-alpha, IFN-gamma, IL-1, IL-2 and IL-8 and is the underlying immune mechanism of psoriasis, alopecia areata, rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin-dependent diabetes mellitus and experimental autoimmune uveitis (EAU). Type 2 immune response is seen in antibody-mediated autoimmune diseases. Based on the pharmacokinetic effects of cetirizine and allopurinol, this paper introduces these two safe and inexpensive drugs as novel potential agents against cell-mediated autoimmune disorders. Cetirizine, supposed to inhibit DNA binding activity of NF-kappa B, inhibits the expression of adhesion molecules on immunocytes and endothelial cells and the production of IL-8 and LTB4, two potent chemoattractants, by immune cells. It induces the release of PGE2, a suppressor of antigen presentation and MHC class II expression, from monocyte/macrophages and reduces the number of tryptase positive mast cells in inflammation sites. Tryptase is a chemoattractant, generates kinins from kininogen, activates mast cells, triggers maturation of dendritic cells and stimulates the release of IL-8 from endothelial cells and the production of Th1 lymphokines by mononuclear immunocytes. Allopurinol is a free radical scavenger, suppresses the production of TNF-alpha and downregulates the expression of ICAM-1 and P2X(7) receptors on monocyte/macrophages. ICAM-1 serves as a ligand for LFA-1 (on T lymphocytes), allowing proper antigen presentation. P2X(7) receptors are thought to be involved in IL-1beta release, mitogenic stimulation of T lymphocytes and the probable cytoplasmic communication between macrophages and lymphocytes at inflammation sites. Allopurinol was markedly more effective than prednisolone in treating experimental autoimmune uveitis and in combination with cyclosporine suppressed the inflammatory reaction of this condition more effectively than either agent alone. As allopurinol is a competitive inhibitor of xanthine oxidase and decreases serum levels of uric acid, which is protective against multiple sclerosis, it should preferably be coadministered with uric acid precursors in the treatment of this condition. Cetirizine and allopurinol may prove of benefit in the treatment of various cellular autoimmune disorders.
14963200 Maintenance of remission with leflunomide in Wegener's granulomatosis. 2004 Mar OBJECTIVE: To investigate the safety and efficacy of leflunomide plus low-dose prednisolone for the maintenance of remission in Wegener's granulomatosis (WG). METHODS: This was a Phase II, single-centre, open-label clinical investigation of patients with generalized WG treated with leflunomide after the induction of complete (n = 4) or partial (n = 16) remission by cyclophosphamide/prednisolone combination therapy. Leflunomide treatment was initiated at 20 mg/day and increased to 30 mg/day after 12 weeks and, in patients with partial remission, to 40 mg/day after 24 weeks. Concomitant low-dose prednisolone (< or =10 mg/day) was allowed during the study. In addition to the frequency of relapse, treatment efficacy was assessed by the standard measures of disease activity/extent. RESULTS: A total of 20 patients were enrolled in the trial. During a treatment period of up to 2.5 yr (median 1.75 yr, range 1-2.5 yr), one patient had a major relapse and required retreatment with cyclophosphamide/prednisolone. Eight patients had minor relapses that were successfully treated by dose increases to 40 mg/day leflunomide. Disease activity remained unchanged for the duration of the study. The most frequently reported adverse events were mild respiratory infection (40%), arthralgia (35%) and hypertension (35%); dry skin, nail disorder and diarrhoea were each reported by 30% of patients. Despite the aggressive pretreatment with cyclophosphamide, adverse events with leflunomide treatment at the higher dose (30-40 mg/day) were comparable with those seen with the standard dose (20 mg/day) for rheumatoid arthritis patients. CONCLUSION: Leflunomide appears to be safe and well tolerated for the maintenance of complete or partial remission of WG. The results of this pilot study encourage further controlled trials comparing leflunomide with alternative remission maintenance therapies.
14760803 ADAMTS-1, a gene product of articular chondrocytes in vivo and in vitro, is downregulated 2004 Feb OBJECTIVE: Osteoarthritic (OA) cartilage degeneration and cartilage destruction in rheumatoid arthritis depends significantly on enzymatic degradation of cartilage proteoglycan aggrecan. A member of the ADAMTS family of proteases, ADAMTS-1 was described to have "aggrecanase" activity. We investigated the quantitative expression and distribution of ADAMTS-1 in healthy and OA cartilage and in cultured articular chondrocytes with and without stimulation by interleukin 1beta (IL-1beta) and insulin-like growth factor-I (IGF-I). METHODS: Conventional and online polymerase chain reaction (PCR) technology was used to determine ADAMTS-1 mRNA expression levels of ADAMTS-1. Protein was localized using immunostaining with different polyclonal antibodies. RESULTS: Conventional and online semiquantitative PCR showed significant levels of ADAMTS-1 mRNA expression in normal and OA chondrocytes in vivo and in vitro. Only a slight increase was observed in OA cartilage. After stimulation with IL-1beta a downregulation of ADAMTS-1 was observed, whereas IGF did not appear to change mRNA expression levels in vitro. The in vivo mRNA expression results were confirmed by the presence of significant protein staining with antibodies for ADAMTS-1 in normal and OA chondrocytes as well as Western blotting analysis. Whereas a significantly stronger stain was seen in normal articular cartilage in the upper zones, in OA cartilage as well the middle zone showed enhanced staining. CONCLUSION: Our results confirm the expression and presence of ADAMTS-1 in articular cartilage. However, they also point out that ADAMTS-1 appears to be constitutively expressed by adult articular chondrocytes and overall is not strongly upregulated in OA. Thus our data suggest that ADAMTS-1 is the first matrix-degrading enzyme downregulated by the catabolic factor IL-1beta in vitro.
14690142 Receptor activator of nuclear factor kappaB ligand is expressed in resident and inflammato 2003 OBJECTIVE: The pathogenesis of periprosthetic bone loss in aseptic and septic prosthesis loosening is unclear. There is considerable evidence that macrophages and osteoclasts play a key role in focal bone erosion and osteolysis around the prosthesis. RANKL (receptor activator of nuclear factor kappaB ligand) was shown to be a potent osteoclastogenic factor, and to be involved in bone destruction of myeloma and rheumatoid arthritis patients. Osteoprotegerin (OPG) is the natural RANKL inhibitor and may prevent periprosthetic bone loss. METHODS: The presence and distribution of RANKL, its receptor RANK and OPG in the periprosthetic interface of septically (n = 5) and aseptically (n = 6) loosened prostheses was examined by immunohistochemistry and immunoblotting. Additionally, the immunophenotype of the inflammatory infiltrate was determined [CD3, CD68, Ki-67, tartrate-resistant acid posphatase (TRAP)]. RESULTS: Aseptic and septic cases revealed a different histopathologic pattern. However, in all cases RANKL and RANK could be demonstrated in macrophages and giant cells. In addition, RANKL detected by immunoblot analysis proved to have the same molecular weight as a recombinant RANKL used as a control (31 kD and approximately 48 kD). OPG was detected in aseptic loosening, where macrophages showed a strong staining, but multinucleated giant cells were only weakly stained. A weak OPG staining was also observed in septic loosening. CONCLUSION: The pathogenesis of bone loss in septic loosening remains unclear, because the septic membrane bears few macrophages and giant cells, and half of them express OPG. In aseptic loosening, macrophages might not be stimulated by RANKL as a result of OPG expression. But multinucleated giant cells may be activated, as they hardly express OPG. They might be responsible for periprosthetic bone loss in aseptic loosening as a result of their RANKL and RANK expression.