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ID PMID Title PublicationDate abstract
17040963 Increase of B cell-activating factor of the TNF family (BAFF) after rituximab treatment: i 2007 May BACKGROUND: The cytokine B cell-activating factor of the TNF family (BAFF) is involved in the pathogenesis of autoimmune diseases. OBJECTIVE: To access changes in serum protein and mRNA levels of BAFF after rituximab treatment. METHODS: Serum and peripheral blood mononuclear cells (PBMCs) were isolated from five patients (two with lupus, two with Sjögren's syndrome, one with rheumatoid arthritis) before and 12 weeks (range 7-17) after a first course of rituximab infusion. Monocytes and B cells were selected from healthy controls and cocultured for 72 h. BAFF protein and mRNA levels were assessed by ELISA and real-time PCR, respectively. RESULTS: After rituximab treatment, median serum BAFF protein level and BAFF to actin mRNA ratio in PBMCs significantly increased. In monocytes cocultured with autologous B cells, BAFF protein level decreased, whereas the mRNA level was stable. In one closely monitored patient, the mRNA ratio of BAFF to actin in PBMCs increased later than the BAFF serum level. CONCLUSIONS: Two distinct mechanisms are probably involved in the increase in BAFF level after B cell depletion: (1) the decrease in its receptors leading to a release of BAFF; (2) a delayed regulation of BAFF mRNA transcription. This could favour the re-emergence of autoreactive B cells.
16924694 Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumato 2006 Dec OBJECTIVE: To compare the diagnostic utility of anti-cyclic citrullinated peptide (anti-CCP) antibodies with other serological markers including rheumatoid factor (RF), anti-agalactosyl immunoglobulin G (IgG) antibody, and matrix metalloproteinase (MMP)-3 in very early rheumatoid arthritis (RA). METHODS: Serum concentrations of anti-CCP antibodies, RF, anti-agalactosyl IgG antibody, and MMP-3 were measured in 262 patients with RA ("total RA") including 55 patients with disease duration of less than 6 months who had not been treated before entry ("very early RA") and 116 patients with rheumatic diseases other than RA. RESULTS: The diagnostic sensitivity of anti-CCP antibodies was 82.4% in total RA and 67.3% in very early RA and was lower than that of RF (84.0% total RA, 83.6% very early RA) and anti-agalactosyl IgG antibody (90.5%, 90.9%), whereas specificity, positive predictive value, and diagnostic accuracy were the best among markers tested both in total RA and in very early RA. The presence of either anti-CCP antibodies or RF increased the sensitivity, but any combination of serological markers was not significantly better in diagnostic accuracy than anti-CCP antibodies alone. The rates of RF-positive subjects in anti-CCP antibody-negative patients both in total RA (43.5%) and in very early RA (61.1%) were higher than those of anti-CCP antibody-positive subjects in RF-negative patients (38.1% and 22.2%, for total RA and early RA, respectively). CONCLUSION: Measurement of anti-CCP antibodies, by itself, is useful for the diagnosis of RA; however, combined use of anti-CCP antibodies with RF may be more useful than either method alone for the diagnosis of very early RA.
16924455 [A postoperative infectious complication in a patient with rheumatoid arthritis treated wi 2006 Dec Tumor necrosis factor (TNF) blocking agents, such as adalimumab, are well tolerated and provide improvement in the symptoms and signs of rheumatoid arthritis (RA). Due to its immunosuppressive effect, an increased risk of infection has been suggested, but so far no differences between adalimumab and placebo groups have been found in pivotal trials. Patients with RA succumb to postoperative complications because they have a systemic disease and use medication with immunosuppressive effects. We report on a patient with longstanding, active RA who had received adalimumab 40 mg every other week with prolonged infection, wound dehiscence and pseudoarthrosis following reconstructive forefoot surgery due to deformities secondary to RA. The postoperative infection occurred although adalimumab therapy had been stopped 8 days before surgery. The half-life of adalimumab is 10.0-13.6 days following a single intravenous dose. Whether patients under therapy with adalimumab are at an increased risk of developing postoperative complications is unclear, a retrospective analysis of the pivotal studies would be helpful in estimating the risk of perioperative (wound) infections in patients receiving anti-TNF. Moreover, it is not clear when therapy should be stopped prior to surgical intervention. Obviously prospective clinical trials would be more convincing.
16251070 [The study of inhibitory peptides on T cell activation in rheumatoid arthritis]. 2005 Jun 29 OBJECTIVE: To study the inhibitory role of altered HA308 - 317 peptides in T cell responses in patients with rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMC) were obtained from 27 HLA-DRB1 positive RA patients. T cell responses to altered HA308-317 peptides were examined by using (3)H incorporation assay. The level of IL-2 and IFNgamma in the supernatants was identified by an enzyme-linked immunosorbent assay. The CD69 expression on T cell surface was studied by using flow cytometry. RESULTS: Compared to wild type CII263 - 272 or HA308 - 317, altered HA308 - 317 peptides failed to stimulate T cell proliferation (P < 0.05) and production of IL-2 as well as IFNgamma and resulted in lower expression of CD69 in RA patients (P < 0.05). SI values for T cell coincubated with altered HA308 - 317 peptides and CII263 - 272 or wild type HA308 - 317 were significantly lower than coincubated with CII263 - 272 and wild type HA308 - 317 alone (P < 0.05). CONCLUSION: Substitution of TCR-binding residue of HA308 - 317 yielded weak or non-T-cell stimulating peptides, which might be potentially effective in blocking abnormal T cell responses in RA.
16513103 Prevalence of anti-3-nitrotyrosine antibodies in the joint synovial fluid of patients with 2006 Aug BACKGROUND: Increased reactive nitrogen species (RNS) production has been suggested in the pathogenesis of rheumatoid arthritis (RA), osteoarthritis (OA) as well as in systemic lupus erythematosus (SLE). They are known to have direct toxicity to cells. High concentrations of serum nitrite/nitrate and elevated urinary nitrate:creatine ratio has been found in patients with RA, OA and SLE. Reactive nitrogen species play a role in the chronicity of inflammatory reaction such as cartilage and bone destruction seen in patients with RA and OA. Arthritis is also associated with increased intra-articular formation of 3-nitrotyrosine (3-NT), which may contribute to joint damage. There is growing evidence that nitrative injury plays an important role in oxidative stress in the etiology and pathogenesis of SLE. 3-nitrotyrosine is thought to be a relatively specific marker of nitrosative damage mediated by nitric oxide (NO) and its by-products. METHODS: Commercially available poly l-tyrosine was exposed to nitrating species resulting in the formation of 3-nitrotyrosine. Antibodies present in synovial fluid and sera of 30 patients with rheumatoid arthritis, 15 patients with osteoarthritis and 15 patients with SLE were studied for their recognition of 3-NT by direct binding ELISA. RESULTS: IgG from the synovial fluid (SF) of RA and OA patients, purified on protein A-Sepharose matrix, exhibited increased recognition of 3-NT, than the IgG isolated from the sera of RA and OA patients in competitive ELISA, whereas IgG isolated from the sera of SLE patients exhibited increased recognition of 3-NT, than the IgG isolated from the synovial fluid. There was a higher prevalence of antibodies against 3-NT in the synovial fluid than in the sera of patients with RA and OA. Higher level of anti-3-NT antibodies were found in the synovial fluid in the later stages of SLE when compared to the early stages but was not more than that found in the sera. CONCLUSION: The RNS may be produced within the inflamed joints of RA and OA patients but not in SLE patients. The 3-NT levels also correlated directly with disease activity.
15686595 Increased proviral load in HTLV-1-infected patients with rheumatoid arthritis or connectiv 2005 Feb 1 BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) proviral load is related to the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and has also been shown to be elevated in the peripheral blood in HTLV-1-infected patients with uveitis or alveolitis. Increased proliferation of HTLV-1-infected cells in, or migration of such cells into, the central nervous system is also seen in HAM/TSP. In the present study, we evaluated the proviral load in a cohort of HTLV-1-infected patients with arthritic conditions. RESULTS: HTLV-1 proviral load in the peripheral blood from 12 patients with RA and 6 patients with connective tissue disease was significantly higher than that in matched asymptomatic HTLV-1 carriers, but similar to that in matched HAM/TSP controls. HAM/TSP was seen in one-third of the HTLV-1-infected patients with RA or connective tissue disease, but did not account for the higher proviral load compared to the asymptomatic carrier group. The proviral load was increased in the synovial fluid and tissue from an HTLV-1-infected patient with RA, the values suggesting that the majority of infiltrated cells were HTLV-1-infected. In the peripheral blood from HTLV-1-infected patients with RA or connective tissue disease, HTLV-1 proviral load correlated with the percentages of memory CD4+ T cells and activated T cells, and these percentages were shown to be markedly higher in the synovial fluid than in the peripheral blood in an HTLV-1-infected patient with RA. CONCLUSIONS: These biological findings are consistent with a role of the retrovirus in the development of arthritis in HTLV-1-infected patients. A high level of HTLV-1-infected lymphocytes in the peripheral blood and their accumulation in situ might play a central role in the pathogenesis of HTLV-1-associated inflammatory disorders. Alternatively, the autoimmune arthritis, its etiological factors or treatments might secondarily enhance HTLV-1 proviral load.
16646989 Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid ar 2006 We investigated lipid profiles and lipoprotein modification after immuno-intervention in patients with early rheumatoid arthritis (ERA). Fifty-eight patients with ERA who met the American College of Rheumatology (ACR) criteria were included in the study. These patients had disease durations of less than one year and had not had prior treatment for it. Smokers or patients suffering from diabetes mellitus, hypothyroidism, liver or kidney disease, Cushing's syndrome, obesity, familiar dyslipidemia and those receiving medications affecting lipid metabolism were excluded from the study. Sixty-three healthy volunteers (controls) were also included. Patients were treated with methotrexate and prednisone. Lipid profiles, disease activity for the 28 joint indices score (DAS-28) as well as ACR 50% response criteria were determined for all patients. The mean DAS-28 at disease onset was 5.8 +/- 0.9. After a year of therapy, 53 (91.3%) patients achieved the ACR 20% response criteria, while 45 (77.6%) attained the ACR 50% criteria. In addition, a significant decrease in the DAS-28, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were observed. ERA patients exhibited higher serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides, whereas their serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower compared to controls. As a consequence, the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was significantly higher in ERA patients compared to controls. After treatment, a significant reduction of the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was observed, a phenomenon primarily due to the increase of serum HDL-C levels. These changes were inversely correlated with laboratory changes, especially CRP and ESR. In conclusion, ERA patients are characterized by an atherogenic lipid profile, which improves after therapy. Thus, early immuno-intervention to control disease activity may reduce the risk of the atherosclerotic process and cardiovascular events in ERA patients.
16575870 Peripheral blood T lymphocytes from patients with early rheumatoid arthritis express RANKL 2006 Apr OBJECTIVE: To investigate the osteoclastogenic potential of T cells from the peripheral blood (PB) and synovial fluid (SF) of patients with rheumatoid arthritis (RA) on autologous monocytes, and to study the cytokines implicated in this process. METHODS: T cells and monocytes were isolated from the PB of 20 healthy subjects and 20 patients with early RA, and from the SF of 20 patients with established RA. Autologous T cell/monocyte cocultures were established in the absence of exogenous cytokines or growth factors in order to examine spontaneous ex vivo osteoclast differentiation by tartrate-resistant acid phosphatase staining and calcified matrix resorption activity. RESULTS: Surface RANKL was expressed on freshly isolated T cells from the PB of patients with early RA and the SF of patients with established RA. In addition, surface interleukin-15 (IL-15) was detected on freshly isolated T cells and monocytes from the PB of patients with early RA and the SF of patients with established RA. Autologous T cell/monocyte cocultures derived from the SF of patients with established RA and from the PB of patients with early RA, but not from the PB of healthy controls, resulted in osteoclast differentiation that was significantly inhibited by osteoprotegerin (OPG) and by neutralizing monoclonal antibodies to IL-15, IL-17, tumor necrosis factor alpha (TNFalpha), and IL-1beta. OPG, anti-TNFalpha, and anti-IL-1beta demonstrated a cooperative inhibitory effect. At 1-year followup, surface RANKL and IL-15 and ex vivo osteoclastogenesis were no longer observed on PB T cells or monocytes from patients with early RA in whom clinical remission had been achieved with treatment. CONCLUSION: T cells are important contributors to the pathogenesis of bone erosions in RA through interaction with osteoclast precursors of the monocyte/macrophage lineage.
15990992 The inhibitory effect of disease-modifying anti-rheumatic drugs and steroids on gliostatin 2005 Oct Gliostatin/platelet-derived endothelial cell growth factor (GLS/PD-ECGF) is known to have both angiogenic and arthritogenic activities. The purpose of this study was to investigate whether disease-modifying anti-rheumatic drugs (DMARDs) and steroids are involved in the regulation of GLS expression. Fibroblast-like synoviocytes (FLSs) obtained from patients with rheumatoid arthritis (RA) were cultured and stimulated by interleukin (IL)-1beta with or without DMARDs and steroids. The expression levels of GLS were determined using the reverse transcription-polymerase chain reaction and an ELISA. In cultured rheumatoid FLSs, the expression of GLS mRNA was significantly increased by stimulation with IL-1beta. By contrast, GLS mRNA levels in IL-1beta-stimulated FLSs were reduced by treatment with aurothioglucose (AuTG) and dexamethasone (DEX). These findings indicate that AuTG and DEX have anti-rheumatic activity, which is mediated via the suppression of GLS production. Neither methotrexate (MTX) nor sulfasalazine (SSZ) had a significant influence on GLS levels in our study.
17043436 Etanercept-induced systemic lupus erythematosus in a patient with rheumatoid arthritis. 2006 Oct Tumor necrosis factor (TNF) is known to play a critical role in the pathogenesis of rheumatoid arthritis (RA). Etanercept is a recombinant soluble fusion protein of TNF alpha type II receptor and IgG, which acts as a specific TNF-alpha antagonist. Anti-TNF-alpha therapy has been an important advance in the treatment of RA. However, induction of autoantibodies in some proportion of patients treated with TNF alpha inhibitors raised concerns for development of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). Although new autoantibody formation is common with anti-TNF alpha therapy, there are only rare reports of overt SLE, most of which manifested without major organ involvement and resolved shortly after discontinuation of the therapy. We describe a 55-yr-old Korean woman who developed overt life threatening SLE complicated by pneumonia and tuberculosis following etanercept treatment for RA. This case is to our knowledge, the first report of etanercept-induced SLE in Korea.
16247548 Health-related quality of life in rheumatoid arthritis: therapeutic education plus pharmac 2006 Jun OBJECTIVE: To determine whether therapeutic education added to conventional drug therapy reduced disability and pain in patients with early rheumatoid arthritis (RA). METHODS: Fourty-three patients with RA, 29F/14 M, were included in a randomized, controlled trial and assigned to a control group receiving conventional pharmacological treatment only (n=21), or an intervention group receiving therapeutic education added to conventional pharmacological treatment (n=22). The main outcome variable was self-reported disability on the Stanford health assessment questionnaire (HAQ). RESULTS: At 18 months, patients in the intervention group had less disability (HAQ), pain intensity, number of tender and swollen joints, and patient's and physician's global assessments (p=0.003, 0.031, 0.003, 0.001, 0.014, and 0.004, respectively) compared with baseline, and improvements in disability and number of tender and swollen joints (p=0.024, 0.040, and 0.003, respectively), compared with controls. CONCLUSIONS: Patients receiving pharmacological treatment and therapeutic education had a better evolution than those receiving only pharmacological treatment.
16707537 Benefits of a programme taking advantage of patient-instructors to teach and assess muscul 2006 Dec AIM: To evaluate a rheumatoid arthritis patient-instructor-based formation-assessment programme for its ability to improve and assess musculoskeletal knowledge and skills in third-year medical students. METHODS: (1) The quality of our musculoskeletal teaching was assessed before patient-instructor intervention through an open-questions test (pre-test) and performance record forms (PRFs) filled in by the patient-instructors. (2) The improvement afforded by patient-instructors was evaluated through a second (identical) open-questions test (post-test). (3) The resulting skills in the students were further assessed by an individual patient-instructors physical status record form (PSRF), filled in by the students. RESULTS: Pre-tests and post-tests showed an improvement in correct answers from a mean score of 39% to 47%. The history-taking questions that obtained <50% scores in the pre-test mostly dealt with the consequences of a chronic illness. Intervention of patient-instructors especially improved knowledge of the psychosocial aspects and side effects of drugs. With regard to physical examination, patient-instructors makedly improved the identification of assessment of signs of active and chronic inflammation. PRF analysis showed that 10 of 28 questions answered by <50% of the students were related to disease characteristics of rheumatoid arthritis, extra-articular signs, side effects of drugs and psychosocial aspects. Analysis of the PSRF indicated that the weakness of our students' physical examination abilities in particular is related to recognising the types of swelling and differentiating tenderness from pain on motion. CONCLUSION: This study proves the considerable benefits of the involvement of patient-instructors in the teaching and assessment of clinical skills in students.
16370218 [Septic oligoarthritis as a complication of rhumatoid arthritis--a case report]. 2005 Oct We present the case a 53-year-old patient followed-up since 1999, for erosive AR treated with methotrexate and glucocorticoids. In April 2000, he had an arthritis of the right knee. The identification of an enterobacter in blood culture, and synovial biopsy results permitted the diagnosis of septic arthritis. After 23 days of antibioterapy treatment, the patient had an arthritis of the left knee. The infectious origin was confirmed by synovial biopsy. The course was better after adaptation of the antibiotics. Septic arthritis is then a serious complication of AR. It requires a fast and multidisciplinary management. It can be threatenig in fragile and immunocompromised patients. The functional prognosis is especially compromised in polyarticular septic arthritis.
17580556 [Oxycodone: a strong opioid in the treatment of patients with arthritis]. 2006 Reducing pain is a major goal in treating patients with arthritis. Oral controlled-release opioid products enable patients to better maintain pain control due to convenient dosing intervals and sustained blood concentration. Oxycodone is a strong opioid that has proved to be efficacious in analgesic studies of persistent moderate to severe pain in patients with degenerative and inflammatory rheumatic diseases. Beyond significant pain control and better physical function, controlled-release oxycodone improved coping with pain in patients with osteoarthritis.
17158136 IRF5 rs2004640-T allele, the new genetic factor for systemic lupus erythematosus, is not a 2007 Jun BACKGROUND: Recently, a new genetic factor within the interferon regulatory factor 5 (IRF5) gene was demonstrated for systemic lupus erythematosus (SLE) through linkage and association: the rs2004640-T allele. IRF5 is involved in the production of rheumatoid arthritis (RA) cytokines, and SLE already shares with RA one genetic factor within the tyrosine phosphatase PTPN22 gene. AIM: To test the hypothesis that the SLE IRF5 genetic factor could also be shared with RA. PATIENTS AND METHODS: 100 French Caucasian trio families with RA were genotyped and analysed with the transmission disequilibrium test, the frequency comparison of the transmitted and untransmitted alleles, and the genotype relative risk. 97% power was available to detect at least a trend in favour of a factor similar to that reported for SLE. RESULTS: The analysis showed the absence of linkage and association globally and in "autoimmune" RA subsets, with a weak non-significant trend against the IRF5 rs20046470-T allele. Given the robustness of familial-based analysis, this slight negative trend provided strong evidence against even a weaker factor than that reported for SLE. CONCLUSION: Our results exclude the IRF5 rs2004640-T allele as a major genetic factor for RA in this French Caucasian population.
16150720 Vasoactive intestinal peptide induces regulatory dendritic cells with therapeutic effects 2005 Sep 20 The induction of antigen-specific tolerance is critical for the prevention of autoimmunity and maintenance of immune tolerance. In addition to their classical role as sentinels of the immune response-inducing T cell reactivity, dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction/activation of regulatory T cells (Tr). The possibility to generate tolerogenic DCs opens new therapeutic perspectives in autoimmune/inflammatory diseases. Therefore, the characterization of the endogenous factors that contribute to the development of tolerogenic DCs is highly relevant. In this study, we report on the use of the known immunosuppressive neuropeptide, the vasoactive intestinal peptide, as a new approach to induce tolerogenic DCs with capacity to generate Tr cells, to restore tolerance in vivo, and to reduce the progression of rheumatoid arthritis and experimental autoimmune encephalomyelitis.
16052323 Quantitative immunodetection of key elements of polyphosphoinositide signal transduction i 2005 Aug Phosphoinositides play an essential role in diverse cellular functions such as cell proliferation, cytoskeletal regulation, intracellular vesicle trafficking, motility, cell metabolism and death. Alteration of these pathways is common to many diseases. In this study, we show that osteoblasts from patients affected by osteoarthritis (OA) and by rheumatoid arthritis (RA) present a decreased cell proliferation and a reduced expression of the key elements of polyphosphoinositide signal transduction such as phosphatidylinositol-3-kinase (PI 3K), phospholipase C gamma1 (PLCgamma1), and protein kinase C zeta (PKCzeta) compared to the post-traumatic (PT) patients. Our results suggest that a correlation may exist between the reduced osteoblast proliferation observed in OA and RA patients and the lowered expression of PI 3K, PLCgamma1, and PKCzeta enzymes. The reduced proliferation rate of osteoblasts in response to these signal transduction effectors could counteract the evolution of arthritic disease.
16142857 Current tumor necrosis factor-alpha inhibitor use is associated with a higher probability 2005 Sep OBJECTIVE: To determine if current tumor necrosis factor-alpha (TNF-alpha) inhibitor use is associated with a higher probability of remission than non-use in patients with rheumatoid arthritis (RA). METHODS: Clinical and demographic data were collected from 322 patients with RA during regularly scheduled clinic visits. Current and past medications were recorded. Disease activity status (remission or not) was determined using American College of Rheumatology preliminary criteria for clinical remission of RA. A logistic regression analysis was used to calculate crude and adjusted odds ratios (OR) for remission for current TNF-alpha inhibitor users versus non-users. Multivariate analysis included age, gender, race, disease duration, use of nonsteroidal antiinflammatory drugs (NSAID), prednisone dosage, and numbers of previously used disease modifying antirheumatic drugs (DMARD). RESULTS: Of the 111 patients enrolled in the study who were users of TNF-alpha inhibitors, 25.2% were found to be in clinical remission. Of the 211 patients who were non-users, 14.7% were in clinical remission. The unadjusted OR for remission in TNF-alpha inhibitor users was 1.96 (95% confidence interval, CI: 1.10 to 3.48). The adjusted OR was 2.74 (95% CI: 1.40 to 5.34). CONCLUSION: Cross-sectional observations from an outpatient arthritis clinic found a significantly higher remission rate in patients with RA taking a TNF-alpha inhibitor compared to non-users.
15911288 Increased muscle activity to stabilise mobile bearing knees in patients with rheumatoid ar 2005 Jun The aim of this study was to assess the differences in muscle activity (surface EMG) between a posterior stabilised (PS) total knee design and a mobile bearing (MB) posterior cruciate ligament retaining design in rheumatoid arthritis (RA) patients during a step-up task. Four patients with a PS total knee prosthesis and three patients with a MB total knee prosthesis were selected based on pain score, knee function, range of motion and joint stability. Clinical scores and functional scores were comparable between the two groups pre-operatively and at the 1-year follow-up. Visual analysis of the EMG activity of the main flexor and extensor muscles showed that the activity of both extensor and flexor muscles of the MB group was on average higher compared to the PS group. When the maximum activities of the muscles were compared, the patients in the MB group showed a significant higher maximum peak activity (p<0.05) of the Vastus Medialis (VM), Vastus Lateralis (VL) and Semitendinosus (ST) during step-up than the patients in the PS group. Also the instance of activation of the Vastus Medialis and the Vastus Lateralis was significant earlier in the MB group compared to the PS group. Since the differences between the PS and the MB group did not only show an increase of muscle activity but also an earlier activation of the flexor muscles, this may express compensation by coordination. Rehabilitation programs for RA patients should include besides muscle strength training, elements of muscle-coordination training.
15642135 Circulating tumour necrosis factor-alpha bioactivity in rheumatoid arthritis patients trea 2005 Our objective was to clarify the heterogeneity in response to infliximab treatment in rheumatoid arthritis (RA); to this end, a bioassay was designed to explore the contribution of circulating tumour necrosis factor (TNF)-alpha bioactivity and its possible link to response. The bioassay is based on the induction of IL-6 and osteoprotegerin (OPG) production by synoviocytes in response to TNF-alpha. RA synoviocytes were cultured with TNF-alpha (5 ng/ml) and 42 RA plasma samples collected just before starting therapy. Levels of IL-6 and OPG were measured in supernatants. In 20 of the patients, plasma samples collected before and 4 hours after the first and the ninth infusions were tested in the same way. Plasma concentrations of TNF-alpha and p55 and p75 soluble receptors were measured using ELISA. TNF-alpha induced IL-6 and OPG production by synoviocytes, which was further increased with patient plasma dilutions and inhibited by infliximab. With plasma samples obtained before the first infusion, the IL-6-induced production was greater in patients with a good clinical response than in the poor responders (44.4 +/- 23.3 ng/ml versus 27.4 +/- 20.9 ng/ml; P = 0.05). This high circulating TNF-alpha bioactivity was strongly inhibited with the first infliximab infusion. The difference between IL-6 levels induced with plasma samples obtained before and 4 hours after the first infusion was greater in patients with a good clinical response (40.0 +/- 23.7 ng/ml versus 3.4 +/- 10.0 ng/ml; P = 0.001). Similar findings were obtained for OPG production (7.0 +/- 6.2 ng/ml versus 0.0 +/- 3.0 ng/ml; P < 0.05). Levels of circulating TNF-alpha bioactivity were predictive of clinical response to TNF-alpha inhibition, confirming a key role for TNF-alpha in these RA patients.