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ID PMID Title PublicationDate abstract
12365719 Prednisolone induces interleukin-18 expression in mononuclear blood and myeloid progenitor 2002 Sep OBJECTIVE: Interleukin (IL)-18 is involved in host defense mechanisms and inflammatory diseases, among them rheumatoid arthritis (RA). High levels of IL-18 expression in RA joints are contrasted by reduced IL-18 expression in RA peripheral blood mononuclear cells (PBMC). Here, we investigated a putative IL-18 regulating role of corticosteroids. METHODS: IL-18 transcript and protein levels in PBMC from untreated and prednisolone treated RA patients, and from healthy donors were assessed by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting. IL-18 regulation was determined in PBMC and U937 cells upon exposure to prednisolone in vitro by RT-PCR and Northern Blot analysis, by ELISA in cell culture supernatants, and in transiently transfected THP-1 cells by IL-18 promoter activity luciferase assays. RESULTS: In RA PBMC, IL-18 transcript levels were dose dependently restored, in parallel with administered prednisolone treatment, to subnormal levels. The corresponding intracellular IL-18 deposits in contrast were depleted. In cultured PBMC and promonocytic cell lines, prednisolone up-regulated IL-18 transcription in parallel with increasing the IL- 18 protein release into cell culture supernatants. CONCLUSION: Prednisolone increases IL-18 expression and release in PBMC and monocytic cell lines.
12726776 Hyper nuclear acetylation (HNA) in proliferation, differentiation and apoptosis. 2003 Jul Coactivators such as cyclic AMP-response-element binding protein (CREB)-binding protein (CBP) and p300/CBP associated factor (P/CAF) play a crucial role in coordinating and cointegrating eukaryotic transcription. One of the recent paradigms in the eukaryotic transcription field is the finding of molecular basis of coactivator function. The well characterized coactivators such as CBP and P/CAF have been proposed to coactivate/cointegrate gene expression with many transcription activators through two mechanisms. One is complex formation with the components with basal transcriptional machinery. Another is its intrinsic and associated enzymatic activity, which transfers an acetyl-base to the epsilon ( epsilon ) portion of lysine-residues in histones and certain nuclear proteins (factor acetyltransferases; FATs), such as p53, lymphoid enhancer-binding factor (LEF), and transcription factor IIE (TFIIE), which often results in increased transcriptional activity. Recently, the status of hyper nuclear acetylation (HNA) has been thought to influence proliferation, differentiation and apoptosis. Furthermore, recent reports showed that histone acetyltransferase (HAT) activity is increased in human disease, such as cancer and atherosclerosis, and studies have shown associations between nuclear acetylation/deacetylation and cell proliferation/differentiation.
15190931 Reaction of peroxynitrite with hyaluronan and related saccharides. 2004 Apr The effects of peroxynitrite on hyaluronan has been studied by using an integrated spectroscopical approach, namely electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), and mass spectrometry (MS). The reaction has been performed with the polymer, the tetrasaccharide oligomer as well as with the monosaccharides N-acetylglucosamine and glucuronic acid. The outcome of the presence of molecular oxygen and carbon dioxide has been also evaluated. Although 1H-NMR and ESI-MS experiments did not revealed peroxynitrite-mediated modification of hyaluronan as well as of related saccharides, from spin-trapping EPR experiments it was concluded that peroxynitrite induce the formation of C-centered carbon radicals, most probably by the way of its hydroxyl radical-like reactivity. These EPR data support the oxidative pathway involved in the degradation of hyaluronan, a probable event in the development and progression of rheumatoid arthritis.
11928379 [Anti-TNF alpha monoclonal antibodies (infliximab) and tuberculosis: apropos of 3 cases]. 2002 Mar INTRODUCTION: Monoclonal TNF alpha antibodies are a new treatment of severe rheumatoid arthritis. One of the possible side effects is the appearance of opportunistic infections. We report here on three cases of disseminated tuberculosis observed in patients undergoing treatment with infliximab. EXEGESIS: A 45-year-old woman, treated with infliximab, was hospitalised after five infusions for fever and dyspnoea. The exams showed pulmonary and peritoneal tuberculosis. The second case is a 75-year-old woman whose symptoms were fever, cough and cervical adenopathy after three infliximab infusions. Diagnosis was disseminated tuberculosis. The third case is a 59-year-old man who was hospitalised for an infectious syndrome with dyspnoea, after two infliximab infusions. We discovered pulmonary tuberculosis. CONCLUSION: These three cases added to the 68 cases of tuberculosis registered with the treatment of infliximab. This confirms the risk of severe opportunist infectious side effects. TNF alpha is a cytokine which has anti-infectious properties. These tuberculoses are severe and generalized. It is recommended to search for an active or latent tuberculosis before beginning treatment with infliximab, and to check these patients frequently.
14982655 The use of modelling to evaluate new drugs for patients with a chronic condition: the case 2004 Mar OBJECTIVES: To address the structural issues relating to mortality and quality of life (QoL) effects and to identify data on the general pattern of QoL of rheumatoid arthritis (RA) patients through a restructured and enhanced version of the Birmingham Preliminary Model (BPM). DATA SOURCES: Electronic databases and a postal survey of current UK rheumatological practice. REVIEW METHODS: The focus for this report was to evaluate two new drugs, etanercept and infliximab [antibodies against tumour necrosis factor (anti-TNFs)], for use in the treatment of RA using the Birmingham Rheumatoid Arthritis Model (BRAM). Having carried out a rapid systematic review of physician surveys of current disease-modifying antirheumatic drugs (DMARDs) usage patterns in adult patients with RA and a postal survey of consultant rheumatologists working in the UK, the drug sequences were then identified for the model. A series of analyses were then run using the model. The issue of specifying the correct comparison in the analysis being undertaken was investigated using two separate analyses: the situation of comparing anti-TNFs with placebo, and the comparison of a sequence using anti-TNFs with a sequence that represents current practice in the UK. RESULTS: Results from the survey of rheumatologists highlighted the fact that RA has different manifestations and responds to different agents in different patients, all of which makes any summary of practice difficult to achieve and open to the criticism of being an oversimplification. However, the findings generally agree with other surveys and trends observed, such as the increasing acceptance of methotrexate as first line drug of choice in patients with RA, especially if the disease is of an aggressive nature. The newer anti-TNF agents have also begun to be incorporated into use. The incremental cost-effectiveness ratios resulting from the use of an inappropriate comparator of placebo were consistently lower than in the base case where appropriate comparator drugs sequences are used. The focus of the BRAM on a drug sequence helped to avoid the incremental cost-effectiveness of new treatments appearing lower than they really are when inappropriate comparators are used. To test the effect on the analysis results of using the disease-modifying antirheumatic sequence that represents current UK practice, the BRAM was run for the strategies representing current UK practice. The results were not very different from the base-case results. CONCLUSIONS: The main achievement of this work was to bring about a more realistic modelling of real-life clinical pathways and events, as it has developed from the BPM to the BRAM. This has been brought about by overcoming structural and data limitations. In addition, the modelling approach reflected in the BRAM is applicable to other chronic conditions, especially those where a sequential approach to therapeutic options exists. The model has been successfully restructured so that different sequences of treatment can readily be considered, including the sequence that best represents current clinical practice in the UK. In addition, the flexibility inherent in using a modelling approach to consider these health policy questions has been demonstrated. One of the key uncertainties that can now be explored concerns the impact of new drugs on disease progression. Current evidence on this is weak, but should new agents demonstrate such a benefit then the BRAM may be a suitable vehicle through which to investigate the costs and full effects. Inevitably, there remain problems and limitations with the BRAM, but these are almost entirely data limitations. As data on these issues become available the BRAM provides a convenient tool through which reanalysis might be undertaken.
14760792 Efficacy and safety of tacrolimus (FK506) in treatment of rheumatoid arthritis: a randomiz 2004 Feb OBJECTIVE: To evaluate the efficacy and safety of tacrolimus (FK506) in patients with active rheumatoid arthritis (RA) exhibiting resistance to disease modifying antirheumatic drug (DMARD) therapy, and to determine the optimal dosage. METHODS: A total of 212 patients with DMARD-resistant RA were enrolled in this double blind, multicenter, randomized, placebo controlled study and allocated to 3 groups. Patients were administered tacrolimus at a dosage of 1.5 mg/day (68 patients) or 3 mg/day (70 patients), or placebo (74 patients), for 16 weeks. They were allowed to continue taking prednisolone (< or = 5 mg/day) and/or one nonsteroidal antiinflammatory drug (NSAID) during the study. Clinical assessment was based on the American College of Rheumatology (ACR) 20% criteria. RESULTS: ACR 20% response rates were higher in both tacrolimus groups (3 mg: 48.3%; 1.5 mg: 24.6%) than in the placebo group (14.1%), with the rate in the 3 mg group significantly higher. There were no significant differences between the tacrolimus groups and placebo group in the incidence of adverse events. The main adverse events in the tacrolimus groups, especially in the 3 mg group, were renal function abnormalities and gastrointestinal symptoms. However, no significant differences were observed among the 3 groups in the incidence of any adverse event except decrease in serum Mg level. CONCLUSION: Our findings demonstrate excellent dose-dependent efficacy of tacrolimus in patients with DMARD-resistant RA and strongly suggest the usefulness of tacrolimus for treatment of RA. The optimal dosage appears to be 3 mg/day in terms of efficacy and safety.
15046433 Hydroxyapatite-coated, cementless total knee replacement in patients aged 75 years and ove 2004 Mar We have carried out a prospective study comparing the results at five years in patients older than 75 years of age undergoing hydroxyapatite-coated, cementless total knee replacement (TKR) with those who were younger. The Knee Society clinical rating scores were recorded before and after operation. Of 559 patients undergoing TKR, 135 were in the elderly age group. The knee scores at five years or more showed comparable results, with patients under 75 years of age reaching a score of 183 and those aged 75 years or over reaching 174. These differences were predominantly due to the functional component of the score. We conclude that elderly patients do just as well as the younger group using this prosthesis.
11966774 Increased expression of pro-inflammatory cytokines and metalloproteinase-1 by TGF-beta1 in 2002 Mar Transforming growth factor (TGF)-beta1 is expressed abundantly in the rheumatoid synovium. In this study, the inflammatory effect of TGF-beta1 in rheumatoid arthritis (RA) was investigated using cultured fibroblast-like synoviocytes (FLS) from RA and osteoarthritis (OA) patients, as well as non-arthritic individuals. mRNA expressions of IL-1beta, tumour necrosis factor (TNF)-alpha, IL-8, macrophage inflammatory protein (MIP)-1alpha and metalloproteinase (MMP)-1 were increased in RA and OA FLS by TGF-beta1 treatment, but not in non-arthritic FLS. Enhanced protein expression of IL-1beta, IL-8 and MMP-1 was also observed in RA FLS. Moreover, TGF-beta1 showed a synergistic effect in increasing protein expression of IL-1beta and matrix metalloproteinase (MMP)-1 with TNFalpha and IL-1beta, respectively. Biological activity of IL-1 determined by mouse thymocyte proliferation assay was also enhanced by 50% in response to TGF-beta1 in the culture supernatant of RA FLS. DNA binding activities of nuclear factor (NF)-kappaB and activator protein (AP)-1 were shown to increase by TGF-beta1 as well. These results suggest that TGF-beta1 contributes for the progression of inflammation and joint destruction in RA, and this effect is specific for the arthritic synovial fibroblasts.
12583167 [Study progress in Sinomenium acutum (Thunb.) Rehd. et Wils]. 2002 Mar This article reviewed the progress in the study of the pharmacognosy, chemical compositions, pharmacological actions and clinical practices of Sinomenium acutum (Thunb.) Rehd. et Wils. An expectation for the further development and utilization of this plant was put forward.
12165799 TNFalpha induces acetylation of p53 but attenuates its transcriptional activation in rheum 2002 Sep Synovial hyperplasia is an important feature of rheumatoid arthritis (RA) and we have reported that several transcription factors were highly activated in rheumatoid synoviocytes. The purpose of this study was to examine nuclear acetylation in synoviocytes as an activation marker and determine its role in cell activation. Autonomous acetylation of approximately 53 and 62 kDa nuclear proteins was detected in rheumatoid synoviocytes by anti-acetylated lysine specific antibody. Furthermore, tumor necrosis factor alpha (TNFalpha), a potent mitogen for synoviocytes, dose-dependently increased their state of acetylation. Immunoprecipitation analysis revealed that 53 kDa acetylated protein (ap53) was identical with p53, a tumor suppressor gene product. Since enhanced p53 binding to the promoter by TNFalpha treatment was detected by gel shift assay, we analyzed p53 promoter activity by reporter assay system. Contrary to enhanced binding activity, the transcriptional activity was attenuated in a TNFalpha concentration-dependent manner. Since p53 activation requires recruitment of CREB binding protein (CBP) as a coactivator, we also examined the effect of CBP on TNFalpha-induced attenuation of p53 promoter activation. Overexpression of CBP induced p53 transcriptional activity and recovery of TNFalpha-induced inhibition. Our results clearly indicate that autonomous nuclear acetylation is characteristically enhanced in rheumatoid synoviocytes and that p53 is one of acetylated protein. Our results also demonstrate that TNFalpha-induced acetylation of p53 attenuated its transcriptional activation via CBP depletion, and that overexpression of CBP enhanced TNFalpha-induced cell death in rheumatoid synoviocytes, suggesting that regulation of transcriptional coactivator become a novel strategy for RA therapy.
12483716 Management of glucocorticoid-induced osteoporosis in patients with rheumatoid arthritis: r 2002 Dec OBJECTIVE: To examine rheumatologists' management practices for patients with rheumatoid arthritis (RA) taking glucocorticoids seen at one academic medical rheumatology practice. METHODS: All patients diagnosed with RA making at least 2 visits to the practice who were noted to be taking glucocorticoids on an index visit in January or February 1999 were included in a retrospective chart review. RESULTS: Of the 623 eligible patients identified with RA, 236 patients were taking glucocorticoids at their index visit and were included in this study. The mean daily dosage of prednisone (or its equivalent) was 8.8 mg and the mean duration of use during the 2-year chart review was 15.4 months. Twenty-three percent of the study population underwent bone densitometry, and 42% were prescribed a medication that reduces bone loss (not including calcium and/or vitamin D). Calcium and/or vitamin D were noted on the medication lists of 25% of patients. Factors associated with not undergoing bone densitometry in adjusted logistic models included male patient sex and premenopausal status in women. No physician factors were significantly related to performing bone densitometry. Variables associated with not receiving prescription treatment of osteoporosis were male patient sex, premenopausal status, and having at least 1 comorbid condition. CONCLUSION: Patients with RA taking oral glucocorticoids did not routinely undergo bone densitometry and/or receive prescription medications for osteoporosis. Men and premenopausal women were less likely to undergo bone densitometry and to receive a prescription medication for osteoporosis than postmenopausal women. Interventions to improve detection and prevention of glucocorticoid-induced osteoporosis are necessary.
12535793 Chemokine receptors in inflammation: an overview. 2003 Feb Chemokine receptors play a key role in directing the migration of inflammatory cells into various injured or infected organs. However, migration of inflammatory cells into tissues can in itself be a cause and amplifier of tissue damage and disease, particularly in chronic autoimmune or allergic disorders. On this basis, much effort is currently devoted at the identification of molecular signals regulating the recruitment of inflammatory cells into tissues and at developing novel strategies to inhibit discrete pathways in this process. Great progress has recently been made in identification of a number of chemokine receptors involved in the process of leukocyte migration. The challenge is now to elucidate the specific contribution and involvement of the different receptors in distinct inflammatory processes and diseases and to prove that interference with any of these pathways may lead to development of novel therapeutics.
12823855 Hormone replacement therapy in rheumatoid arthritis is associated with lower serum levels 2003 Hormone replacement therapy (HRT) modulates the imbalance in bone remodeling, thereby decreasing bone loss. Sex hormones are known to influence rheumatic diseases. The aim of this study was to investigate the effects of HRT on the serum levels of hormones and cytokines regulating bone turnover in 88 postmenopausal women with active rheumatoid arthritis (RA) randomly allocated to receive HRT plus calcium and vitamin D3 or calcium and vitamin D3 alone for 2 years. An increase in estradiol (E2) correlated strongly with improvement of bone mineral density in the hip (P < 0.001) and lumbar spine (P < 0.001). Both baseline levels and changes during the study of IL-6 and erythrocyte sedimentation rate were correlated positively (P < 0.001). HRT for 2 years resulted in an increase of the bone anabolic factor, insulin-like growth factor 1 (IGF-1) (P < 0.05) and a decrease of serum levels of soluble IL-6 receptor (sIL-6R) (P < 0.05), which is known to enhance the biological activity of IL-6, an osteoclast-stimulating and proinflammatory cytokine. Baseline levels of IL-6 and IGF-1 were inversely associated (P < 0.05), and elevation of IGF-1 was connected with decrease in erythrocyte sedimentation rate (P < 0.05) after 2 years. Interestingly, increase in serum levels of E2 was associated with reduction of sIL-6R (P < 0.05) and reduction of sIL-6R was correlated with improved bone mineral density in the lumbar spine (P < 0.05). The latter association was however not significant after adjusting for the effect of E2 (P = 0.075). The influences of IGF-1 and the IL-6/sIL-6R pathways suggest possible mechanisms whereby HRT may exert beneficial effects in RA. However, to confirm this hypothesis future and larger studies are needed.
12892188 Posterior cruciate ligament at total knee replacement. Essential, beneficial or a hindranc 2003 Jul We report the results of a prospective randomised trial which assessed the role of the posterior cruciate ligament (PCL) following total knee replacement (Genesis I; Smith and Nephew, Memphis, Tennessee). Over a four-year period, 211 patients underwent total knee replacement by the senior author (TJW). They were randomised at surgery to have the PCL either retained, excised or substituted with a posterior stabilised insert. If it was not possible to retain the ligament due to soft-tissue imbalance, it was released from its tibial insertion until suitable tension was obtained. This created a fourth group, those who were intended preoperatively to have the ligament retained, but in whom it was partially released as a result of findings at the time of surgery. All patients were evaluated using the Knee Society rating system (adapted from Insall). A total of 188 patients (212 knees) was available for follow-up at a mean of 3.5 years after surgery. Preoperatively, there was a varus deformity in 191 knees (90%) and a valgus deformity in 21 (10%). There were no statistical differences in the knee or function scores or the range of movement between the excised, retained and substituted groups. There were, however, significantly worse knee and function scores in the group in whom the PCL was released (p = 0.002).
12837011 Medication adherence in persons with cardiovascular disease. 2003 Jul The purpose of this investigation was to determine medication adherence rates among 3 groups of elderly individuals 62 years of age or older, experiencing comorbid conditions including at least 1 cardiovascular disorder. Data, taken from a 3-week period, were combined across the groups to calculate the percentage of prescribed doses taken, percentage of days with correct number of doses, and percentage of expected doses with the correct timing of administration. Multiple linear regression also was performed on several sociodemographic variables to determine their ability to predict adherence. Risks for poor adherence and suggestions to increase adherence are presented.
12740337 Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of 2003 Jun BACKGROUND: Previous studies in patients with osteoarthritis have suggested that the selective cyclooxygenase (COX)-2 inhibitor rofecoxib results in less gastrointestinal damage than non-selective non-steroidal antiinflammatory drugs (NSAIDs). This study compared the incidence of endoscopically detected gastroduodenal ulcers in rheumatoid arthritis patients treated with rofecoxib or a non-selective NSAID. METHODS: In this multicentre, randomised, double blind, 12 week study, patients with rheumatoid arthritis were allocated to rofecoxib 50 mg once daily (n=219), naproxen 500 mg twice daily (n=220), or placebo (n=221). Endoscopy was performed at baseline and at six and 12 weeks. Lifetable analysis and log rank tests were used to analyse the incidence of gastroduodenal ulcers > or =3 mm. Gastric or duodenal ulcers > or =5 mm and erosions were also evaluated as secondary end points. Tolerability was assessed by adverse events. RESULTS: The cumulative incidence of ulcers > or =3 mm at 12 weeks was significantly higher in patients on naproxen (25.5%) than in patients receiving rofecoxib (6.8%; difference 18.7% (95% confidence interval (CI) 11.7%, 25.7%); p<0.001) or placebo (2.9%; difference 22.6% (95% CI 16.1%, 29.1%); p<0.001). The difference between rofecoxib (6.8%) and placebo (2.9%) did not reach statistical significance (p=0.066). Results were similar for ulcers > or =5 mm and for mean changes from baseline in the number of gastroduodenal erosions. The overall incidence of clinical adverse events was similar among treatment groups (61% of patients on placebo, 62% in patients on rofecoxib, and 66% in patients on naproxen). CONCLUSIONS: Rofecoxib 50 mg daily (twice the dose recommended for this patient population) resulted in a lower incidence of endoscopically detected gastroduodenal ulcers and erosions than treatment with naproxen 500 mg twice daily.
15672235 Different ELR (+) angiogenic CXC chemokine profiles in synovial fluid of patients with Beh 2005 Dec The aim of the present study was to determine synovial levels of ELR (+) CXC chemokines, known to attract mainly neutrophils to inflamed tissues by binding the neutrophil chemokine receptors CXCR1 and CXCR2 and promoting neovascularization in patients with various inflammatory disorders. The study group consisted of 14 patients with Behçet's disease and nine with familial Mediterranean fever. Fourteen patients with rheumatoid arthritis and 16 with osteoarthritis served as controls. Synovial chemokine levels were measured by two-step sandwich enzyme-linked immunosorbent assay, and significant differences were found in the various chemokines studied. In addition to its angiogenic properties, increased synovial levels of interleukin-8 by attraction of more neutrophils to synovial fluids might also be responsible for the acute synovitis in patients with Behçet's disease. However, the absence of chronic changes with the eventual development of pannus and erosions might result from relatively lower expression of interleukin-8 and the transient, short-lived nature of the arthritis observed in these patients.
12746898 Responses to the proinflammatory cytokines interleukin-1 and tumor necrosis factor alpha i 2003 May OBJECTIVE: To investigate the expression of the novel Ets transcription factor ESE-1 in rheumatoid synovium and in cells derived from joint tissues, and to analyze the role of nuclear factor kappaB (NF-kappaB) as one of the central downstream targets in mediating the induction of ESE-1 by proinflammatory cytokines. METHODS: ESE-1 protein expression was analyzed by immunohistochemistry using antibodies in synovial tissues from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). ESE-1 messenger RNA (mRNA) levels were analyzed by reverse transcriptase-polymerase chain reaction or Northern blotting in human chondrocytes, synovial fibroblasts, osteoblasts, and macrophages, before and after exposure to interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), or lipopolysaccharide (LPS) with or without prior infection with an adenovirus encoding the inhibitor of nuclear factor kappaB (IkappaB). The wild-type ESE-1 promoter and the ESE-1 promoter mutated in the NF-kappaB site were cloned into a luciferase reporter vector and analyzed in transient transfections. Electrophoretic mobility shift assays (EMSAs) and supershift assays with antibodies against members of the NF-kappaB family were conducted using the NF-kappaB site from the ESE-1 promoter as a probe. RESULTS: Immunohistochemical analysis showed specific expression of ESE-1 in cells of the synovial lining layer and in some mononuclear and endothelial cells in RA and OA synovial tissues. ESE-1 mRNA expression could be induced by IL-1beta and TNFalpha in cells such as synovial fibroblasts, chondrocytes, osteoblasts, and monocytes. Transient transfection experiments and EMSAs showed that induction of ESE-1 gene expression by IL-1beta requires activation of NF-kappaB and binding of p50 and p65 family members to the NF-kappaB site in the ESE-1 promoter. Overexpression of IkappaB using an adenoviral vector blocked IL-1beta-induced ESE-1 mRNA expression. Chromatin immunoprecipitation further confirmed that NF-kappaB binds to the ESE-1 promoter in vivo. CONCLUSION: ESE-1 is expressed in synovial tissues in RA and, to a variable extent, in OA, and is specifically induced in synovial fibroblasts, chondrocytes, osteoblasts, and monocyte/macrophages by IL-1beta, TNFalpha, or LPS. This induction relies on the translocation of the NF-kappaB family members p50 and p65 to the nucleus and transactivation of the ESE-1 promoter via a high-affinity NF-kappaB binding site. ESE-1 may play a role in mediating some effects of proinflammatory stimuli in cells at sites of inflammation.
15054157 Patients with systemic lupus erythematosus are deficient in complement-dependent preventio 2004 Jun OBJECTIVE: A functional deficiency of complement has been implicated but not conclusively demonstrated in the pathogenesis of systemic lupus erythematosus (SLE). To test this, we studied several aspects of complement in 44 patients with SLE, 46 patients with rheumatoid arthritis and 102 blood donors. METHODS: Prevention of immune precipitation (PIP) was measured by an enzyme immunoassay, levels of C1q, C4 and C3 by rocket immunoelectrophoresis, C4A, C4B and C3d by enzyme-linked immunosorbent assay (ELISA), complement haemolysis (CH50) by standard methods and C4 allotypes by high-voltage agarose electrophoresis and sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). RESULTS: PIP was significantly reduced in SLE (P<0.001); the defect was revealed by a sensitive assay measuring this function of complement but not by the other tests employed. The patients were clinically well at the time of study, and levels of C3d, which have been shown to correlate with disease activity, were normal. The defect was more common in patients with early disease (P = 0.009), supporting a role in aetiology or early pathophysiology. PIP was positively correlated with levels of C4 (P = 3 x 10(-5)) and in particular the C4A isotype (P = 9 x 10(-10)) whereas C4B was redundant. CONCLUSIONS: Our results reveal a defect in prevention of immune precipitation in SLE that is apparent at an early stage in the disease and correlates with low levels of C4A. These results indicate that subtle deficiencies of complement may predispose to SLE.
14692538 Effective anti-viral therapy for hemophagocytic syndrome associated with B-cell lymphoma. 2003 Oct A rheumatoid arthritis (RA) patient treated with low-dose methotrexate (MTX) therapy suffered from hemophagocytic syndrome (HPS) associated with B-cell lymphoma (B-LAHS). Administration of acyclovir and intravenous immunoglobulin promptly resolved laboratory test abnormalities accompanied with HPS. Moreover, hemophagocytic histiocytes and lymphoma cells in the bone marrow disappeared without anti-cancer therapy. Two months after reintroduction of MTX for RA flare, lymphoma re-grew rapidly without bone marrow involvement and HPS. Two cycles of combination chemotherapy induced the lymphoma to a complete remission/unconfirmed (CRu), but then the chemotherapy was discontinued due to severe side effects. In this case, on the basis of RA and MTX induced immunosuppressive state, Epstein-Barr virus (EBV) infection was associated with the development of HPS and lymphoma. Anti-viral therapy alone was effective against HPS and lymphoma at initial presentation and improved her general condition. This case indicates that anti-cancer therapy should be preceded by anti-viral therapy and withdrawal of immunosuppressive therapy in patients under immunosuppressive therapy, as long as the clinical situation permits.