Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
18835879 Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid a 2008 Dec OBJECTIVES: The heritability of RA has been estimated to be approximately 55%, of which the MHC contributes about one-third. HLA-DRB1 alleles are strongly associated with RA, but it is likely that significant non-DRB1 MHC genetic susceptibility factors are involved. Previously, we identified two three-marker haplotypes in a 106-kb region in the MHC class III region immediately centromeric to TNF, which are strongly associated with RA on HLA-DRB1*0404 haplotypes. In the present study, we aimed to refine these associations further using a combination of genotyping and gene expression studies. METHODS: Thirty-nine nucleotide polymorphisms (SNPs) were genotyped in 95 DRB1*0404 carrying unrelated RA cases, 125 DRB1*0404-carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB1*04. Quantitative RT-PCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2beta and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and beta(2)-microglobulin (B2M) in 31 RA cases and 21 ethnically, age- and sex-matched healthy controls. Synovial membrane specimens from RA, PsA and OA cases were stained by an indirect immunoperoxidase technique using a mouse-anti-human AIF1 monoclonal antibody. RESULTS: Association was observed between RA and single markers or two marker haplotypes involving AIF1, BAT3 and CSNK. AIF1 was also significantly overexpressed in RA mononuclear cells (1.5- to 1.9-fold difference, P = 0.02 vs HPRT, P = 0.002 vs B2M). AIF1 protein was clearly expressed by synovial macrophages in all the inflammatory synovial samples in contrast to the non-inflammatory OA samples. CONCLUSIONS: The results of the genotyping and expression studies presented here suggest a role for AIF1 in both the aetiology and pathogenesis of RA.
17715048 [Diagnostic value of serum anti-cyclic citrullinated peptide antibodies in patients with r 2007 Aug OBJECTIVE: To explore the diagnostic value of serum anti-cyclic citrullinated peptide (Anti-CCP) antibodies in patients with rheumatoid arthritis (RA). METHODS: Anti-CCP antibodies were detected in the serum samples of 120 RA patients, 71 non-RA patients with various rheumatic diseases, and 50 normal controls by enzyme-linked immunosorbent assay (ELISA) using domestic and imported commercial detection kits. Rheumatoid factors (RF) were assayed by immune-nephelometry. The correlation between Anti-CCP and RF in RA diagnosis was analyzed by calculating the area under curve of the receiver operating characteristic (ROC) curve. RESULTS: The positive rates for Anti-CCP, detected using both domestic and imported kits, were 61.7% (74/120) and 69.2% (83/120) in RA group, significantly higher than those in the non-RA group (9.9%, 7/71 and 7.0%, 5/71) and normal control group (both 0, P<0.001). The sensitivities for Anti-CCP and RF were 69.2% and 64.2%, and the specificities were 92.9% and 67.6%, respectively. The positive predictive value was 94.3% for Anti-CCP and 77.0% for RF, whereas the negative predictive value was 64.1% for Anti-CCP and 52.7% for RF. The likelihood ratio (LR) was 9.82 for anti-CCP and 1.98 for RF. The area under curve of ROC for Anti-CCP was 0.829 and 0.740 for RF. Anti-CCP antibodies had greater diagnostic value than RF in RA diagnosis, and Anti-CCP showed significant correlation with RF (r=0.29, P=0.001). CONCLUSION: Anti-CCP antibodies are an excellent serological marker for RA, which shows high diagnostic specificity at early stage, and can increase its diagnostic value when combined with RF detection, but the role of Anti-CCP in the occurrence and prognosis of RA remains to be further investigated.
17491100 Opposing effects of the D70 mutation and the shared epitope in HLA-DR4 on disease activity 2007 Nov BACKGROUND: Certain sequences present in the hypervariable region of human leucocyte antigen (HLA)-DRB1 known as the shared epitope (SE) are hypothesised to increase the risk of rheumatoid arthritis (RA), whereas alleles encoding aspartic acid at position 70 (D70 alleles) may have a protective effect. METHODS: Patient HLA-DRB1 serotypes were assessed and the genotypes encoding the SE motif or the putatively protective D70 motif identified in a large RA cohort. Logistic regression was used to analyse associations of genotype with presence of disease, comorbidities and disease severity, and association between genotype and change in disease activity over time. RESULTS: The 689 patients enrolled had a mean (SD) age of 57.9 (13.7) years and mean (SD) disease duration of 15.3 (12.7) years. In a comparison with 482 ethnicity matched population-based controls, the D70 sequence exerted a strong protective effect (OR = 0.52, p<0.001) that remained significant when the SE at the same locus was accounted for (OR = 0.72, 95% CI 0.60 to 0.86, p<0.001). The SE assessed on all HLA-DRB1 serotypic backgrounds except DR1 was associated with RA susceptibility (additive OR = 2.43, p<0.001). Associations were found between SE and serum levels of rheumatoid factor (p<0.001, with correlation of 0.18) and anti-cyclic citrullinated peptide antibodies (p<0.001, with correlation of 0.25) but not with serum C-reactive protein. CONCLUSION: The D70 allele has a significant protective effect that is mitigated but still significant when the risk effect of the SE at the same locus is taken into account. The presence of the SE on DR4 is associated with greater RA susceptibility and certain disease-activity measures.
17028793 Is three selected parameters adequate to monitor rheumatoid arthritis? 2007 Jun This pilot study was done to choose which among the five core set criteria will have more discriminating ability and which is easy to administer in a clinical setting. Forty-eight patients recently diagnosed to have rheumatoid arthritis (RA) were recruited for the study. They were assessed by a rheumatologist in each visit (initial and after 2 months of treatment), for five core measures: patient assessment, pain (measured on VAS scale), number of tender joints, health assessment questionnaire (HAQ) score, and erythrocyte sedimentation rate (ESR). All patients were treated with methotrexate 7.5 mg per week and hydroxychloroquin 400 mg per day with adequate dose of NSAIDs. Patients with associated conditions like stroke, ischemic heart disease, and other physical comorbidity were excluded. They were categorized as 20, 50, and 70% improvement, if four of the five criteria occur. The Wilcoxon signed rank test and discriminant function analysis were done to identify the order of importance of measures on influencing the outcome. The ESR followed by patient improvement scale showed the least changes, while HAQ showed the highest changes. Discriminate function analysis has been carried out to see which factors influenced in grouping them for responses with post hoc analyses of finding the order of importance of these factors in classifying the response. Pain scale, ESR, HAQ score, patient improvement scale, and tender score were in the decreasing value of importance. The pain scale, HAQ, and ESR, which are more objective and discriminate measures, are useful as measures in RA.
17165577 [Progress in research on mechanisms of anti-rheumatoid arthritis of triptolide]. 2006 Oct Extracts of Tripterygium wilfordii are effective in traditional Chinese medicine for treatment of rheumatoid arthritis (RA). Triptolide, a diterpenoid triepoxide purified from TWHF, has been identified as the major component of TWHF and might account for its therapeutic effects. To make for the clinical reasonable application and further development of triptolide, in this review was introduced the recent ten-years progress in mechanisms of anti-RA of it, including immunosuppression, anti-inflammation, inducing cell apoptosis, inhibiting vascular proliferation, protecting article cartilage and gene regulation. Triptolide is a potent immunosuppressant.
18853167 Incidence of rheumatoid arthritis from 1995 to 2001: impact of ascertainment from multiple 2009 Feb The aim of this study was to describe the mean incidence rate of rheumatoid arthritis over a 7-year period from 1995 to 2001 in a population in the southern part of Denmark, using the data from several sources. Cases fulfilling the 1987 American College of Rheumatology criteria for rheumatoid arthritis were identified at hospitals and private practising rheumatologists (referral centres), and in general practice. The observed incidence was 32/100,000 person-years (95% confidence interval 29-35). Using the ratio between the number of cases known only from general practice and the number known from general practice and referral centres, the estimated incidence was 35/100,000 person-years (95% confidence interval 32-38). We suggest that the estimated rate should be viewed as a plausible upper limit for the incidence of rheumatoid arthritis in the southern part of Denmark.
17549723 Synovial fluid recruits human mesenchymal progenitors from subchondral spongious bone marr 2007 Oct Microfracture is a frequently used reparative technique that induces a healing response in articular cartilage defects. Penetration of the subchondral bone leads to blood clot formation, allows multipotent mesenchymal cells to access the defect and, subsequently, leads to cartilaginous repair tissue. The aim of our study was to analyze the chemotactic recruitment of human subchondral spongious bone marrow-derived cells by synovial fluid (SF) from normal donors (ND), patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Subchondral spongious bone marrow-derived mesenchymal progenitors were isolated from bone cylinders after high tibial osteotomy and analyzed for the presence of stem cell-related cell surface antigens by flow cytometry. Recruitment of subchondral progenitors by normal SF and SF from donors with degenerated joint diseases was documented by using a modified Boyden chamber chemotaxis assay. The chemotaxis assay demonstrated that synovial fluid has the potential to recruit mesenchymal progenitors in vitro. SF from normal donors and patients with OA showed no difference in the potential to stimulate cell migration. SF obtained from RA donors showed significantly reduced cell recruitment compared to SF derived from OA patients (p = 0.0054) and normal donors (p < 0.0001). The chemotactic activity of SF obtained from normal donors and from patients with degenerative joint diseases suggests that SF may be actively involved in the migration of progenitors in cartilage defects after microfracture.
17363440 Coccidioidomycosis in rheumatology patients: incidence and potential risk factors. 2007 Sep Coccidioidomycosis is a potentially serious fungal infection contracted in endemic areas of the desert southwestern United States. Limited information exists about its incidence and clinical course in patients with rheumatic diseases, who may be at higher risk of symptomatic or disseminated coccidioidomycosis because of either the rheumatic disease itself or its treatment. We analyzed the incidence and risk factors for symptomatic and complicated coccidioidomycosis in our academic rheumatology practice in central Arizona. Between January 1, 2000, and June 30, 2006, coccidioidomycosis was diagnosed in 1.9% of the overall practice and in 3.1-3.6% of patients with rheumatoid arthritis (RA). The annual incidence was 1% in patients recently diagnosed with RA and 2% among patients with recently initiated infliximab treatment. Coccidioidomycosis was identified only in patients with inflammatory rheumatic diseases and extrathoracic dissemination occurred only to joints in two patients. Corticosteroids, immunosuppressive medications, and tumor necrosis factor inhibitors (TNFIs) appeared to be risk factors for symptomatic, but not disseminated coccidioidomycosis.
18257832 Benefit-finding among people with rheumatoid arthritis in Japan. 2008 Mar The realization of positive life influences resulting from the experience of chronic illness has been conceptualized as "benefit-finding". This study of individuals with rheumatoid arthritis in Japan aimed to describe the nature of benefit finding; examine its predictive social factors and evaluate its impact on mental health. A web-based questionnaire was conducted, with valid responses obtained from 364 persons aged 20-59 years. The results indicated that a majority of the participants reported engaging in some type of benefit-finding. "Developing compassion towards others" and "an appreciation of things not previously important" were the most commonly reported. The patients reporting larger emotional support networks and those performing more self-care activities reported achieving higher levels of benefit-finding. Of all the factors examined, benefit-finding was the most significant predictor of mental health. These results expand the base of knowledge regarding living with rheumatoid arthritis and offer practical suggestions for the promotion of well-being.
17765837 Surgery of the lesser toes in rheumatoid arthritis: metatarsal head resection. 2007 Sep This review article discusses the pathologic and anatomic basis of rheumatoid lesser toe deformities. It covers the history of lesser metatarsal head resection being used in its treatment and the theoretic basis behind differing techniques and their relative results and complications. The authors also present their preferred technique for lesser metatarsal head resection.
17414957 The role of T cells in rheumatoid arthritis: new subsets and new targets. 2007 May PURPOSE OF REVIEW: To update the knowledge on the contribution of T cells in rheumatoid arthritis, a selection of publications between the end of 2005 and 2006 were reviewed. RECENT FINDINGS: Th17 cells driven by TGF-beta, IL-1, IL-6 and IL-23 challenge previous concepts of 'Th1'-induced rheumatoid arthritis. Other advancements in IL-17 studies include novel concepts on the IL-17 receptor and additional information on the mechanism of IL-17-induced effects. Regulatory T cells fail to control disease due to defective function secondary to the synovial inflammatory milieu. The predominance of pathogenic effector T cells in the presence of impaired T-cell regulatory mechanisms may therefore contribute to rheumatoid arthritis chronicity. Cellular therapies attempt to restore the balance that includes production of immunoregulatory cytokines such as IL-4 or IL-10. Better T-cell-targeted therapies controlling costimulation are in place with purported increased efficacy and durability, including anti-tumour necrosis factor nonresponders. Additional direct and indirect T-cell approaches include antagonism of T-cell-derived cytokines, T-cell activation or B-cell ablation. SUMMARY: A renewed interest in T cells comes from the discovery of Th17 in rheumatoid arthritis and from novel findings on the role of T cells in rheumatoid arthritis induction, chronicity and relapse.
19028372 Smoking and inflammatory diseases. 2008 Oct Smoking has an impact on the development and outcome of rheumatoid arthritis (RA) and lupus. In RA, smoking is associated with the development of the anti-cyclic citrullinated peptide (CCP2)-positive subset. This risk is increased in heavy smokers carrying at least one copy of the HLA DRB1 shared epitope (SE) alleles. Whereas this interaction between smoking and SE relevant in northern Europe, discrepant results have been observed in other geographic locations, suggesting the involvement of other environmental stimuli and/or gene polymorphisms. There is no interaction between tobacco exposure and PTPN22 1858T for the development of anti-CCP-positive or anti-CCP-negative RA. A strong association exists between smoking and the occurrence of extra-articular manifestations (subcutaneous nodules and cardiovascular events), but smoking has no influence on radiographic outcome. In lupus, tobacco exposure has an impact on the production of anti-double-stranded Desoxyribonuclic (dsDNA) and possibly on the development of the disease, as well as on disease activity/severity. In both diseases, smoking might interfere with drug efficacy.
19099154 Anti-cyclic citrullinated peptide antibodies and rheumatoid factor in leprosy patients wit 2008 Nov The objective of the present research was to evaluate the usefulness of anti-cyclic citrullinated peptide (anti-CCP) antibodies and the IgM rheumatoid factor (IgM RF) test for the differential diagnosis of leprosy with articular involvement and rheumatoid arthritis (RA). Anti-CCP antibodies and IgM RF were measured in the sera of 158 leprosy patients (76 with and 82 without articular involvement), 69 RA patients and 89 healthy controls. Leprosy diagnosis was performed according to Ridley and Jopling classification criteria and clinical and demographic characteristics of leprosy patients were collected by a standard questionnaire. Leprosy patients with any concomitant rheumatic disease were excluded. Serum samples were obtained from all participants and frozen at -20 degrees C. Measurement of anti-CCP antibodies and IgM RF were performed by ELISA, using a commercial second-generation kit, and the latex agglutination test, respectively. Anti-CCP antibodies and IgM RF were detected in low frequencies (2.6 and 1.3%, respectively) in leprosy patients and were not associated with articular involvement. Among healthy individuals both anti-CCP antibodies and IgM RF were each detected in 3.4% of the subjects. In contrast, in the RA group, anti-CCP antibodies were present in 81.2% and IgM RF in 62.3%. In the present study, both anti-CCP antibodies and IgM RF showed good positive predictive value for RA, helping to discriminate between RA and leprosy patients with articular involvement. However, anti-CCP antibodies were more specific for RA diagnosis in the population under study.
17610313 Etanercept-related extensive pulmonary nodulosis in a patient with rheumatoid arthritis. 2007 Jul Although nodulosis is a common extraarticular manifestation of rheumatoid arthritis, accelerated pulmonary nodulosis is a rare event. The etiology of rheumatoid nodules is still unknown. Nodulosis is not necessarily associated with active joint inflammation, suggesting different pathogenic mechanisms for nodule formation and synovial tissue inflammation. We describe a patient with extensive pulmonary nodulosis, probably related to etanercept treatment. Our case emphasizes the need for careful monitoring for adverse events during treatment with biologicals, especially since the differential diagnosis often includes a broad spectrum of diseases.
16572283 Autoantibodies in rheumatoid arthritis: association with severity of disease in establishe 2007 Feb INTRODUCTION: Autoantibodies in rheumatoid arthritis (RA) are useful both for diagnosis and prognosis. Antibodies directed against citrullinated antigens have recently been shown to predict development of RA as well as poor outcome in early arthritis. Data on their role in established RA is limited. We studied the association of various autoantibodies in RA with its severity. MATERIALS AND METHODS: A total of one hundred and twenty nine-patients with established RA was enrolled and sera were collected and stored at -70 degrees C. Data regarding erosions, deformities, and extra-articular features were collected. IgM rheumatoid factor (RF) was measured using nephelometry and value above 20 U was considered positive. IgA RF was measured by enzyme-linked immunosorbent assay (ELISA) and value above the mean+/-2 SD of normal healthy control was taken as positive. Anti-keratin antibody (AKA) was detected by indirect immunofluorescence assay using rat esophagus as substrate. Anti-cyclic citrullinated peptide (CCP) antibodies were measured by commercial ELISA and a value above 5 U was considered as positive. RESULTS: The prevalence of various autoantibodies was: IgM RF 82.2%, anti-CCP antibodies 82.2%, AKA 51.9%, and anti IgA RF 45%. The concordance rate of anti-CCP antibodies with IgM RF was 83%, with AKA 68%, and with IgA RF 60.5%. All but one patient positive for AKA were positive for anti-CCP antibodies. The presence of IgM RF, AKA, and anti-CCP antibody was associated with joint erosions and deformities. None of the antibodies had any association with presence of extra-articular features. No association of IgA RF was seen with erosions, deformities, or extra-articular features. Among 23 seronegative RA patients, 11 were positive for anti-CCP antibodies and 6 were AKA positive. The presence of anti-CCP antibodies was associated with presence of deformities (p<0.05). CONCLUSION: Anti-CCP antibodies are present in majority of patients with established RA including seronegative patients. Both anti-CCP and AKA, in addition to conventional marker like IgM RF, are associated with severe erosive disease.
17404476 [Osteoclast differentiation and activation]. 2007 Apr In autoimmune arthritis, activation of T cells induces bone destruction through receptor activator of NF-kappaB ligand (RANKL) . Recent study revealed interleukin-17 (IL-17) -producing helper T cell subset (Th17) , but not IFN-gamma-producing Th1, to be responsible for bone destruction. Here we summarize the current understanding of osteoclast differentiation and activation in the context of osteoimmunology.
17450763 [Guidelines for the use of biologic therapies in rheumatoid arthritis--December 2006 updat 2007 Jan The authors present the revised version of the Portuguese Society of Rheumatology (SPR) guidelines for the treatment of rheumatoid arthritis (RA) with biological therapies. In these guidelines the criteria for introduction and maintenance of biological therapies were discussed as well as the contra-indications and procedures in case of non-responders. Biological treatment is indicated in RA patients with a disease activity score 28 (DAS 28) superior to 3,2 despite treatment with 20mg/week of methotrexate (MTX) for at least 3 months or, if such treatment is not possible, refractory to 6 months of other conventional disease modifying drug or combination therapy. It is also considered the hypothesis of starting a biological treatment in RA patients treated by the previous regimes with a DAS28 score between 2,6 and 3,2 and a significative functional or radiological worsening. The follow-up should be performed each 3 months. The response criteria, at the end of the first 3 months of treatment, is a decrease of 0,6 in the DAS28 score. After 6 months of treatment response criteria is defined as follows: for those with an initial DAS28 score superior to 5,1, a reduction of the DAS28 score below 4 is required; for those with an initial DAS28 score inferior to 5,1, a reduction of the DAS28 score below 2,6 or between 2,6 and 3,2 without a significative functional or radiological worsening is required. Non-responders, in accordance to the Rheumatologist's clinical opinion, should try a switch to other tumour necrosis factor alpha antagonist or to rituximab.
16956428 Homocysteine enhances cytokine production in cultured synoviocytes from rheumatoid arthrit 2006 Jul OBJECTIVE: Hyperhomocysteinemia is commonly observed in Rheumatoid Arthritis (RA) patients, thus putatively accounting in part for the high rate of cardiovascular events in these subjects. Homocysteine (Hcy) is known to exert a pro-inflammatory effect putatively contributing to the progression of atherosclerotic lesions by cytokine production from several vascular cell-types. In order to evaluate the possibility that Hcy may play a direct pro-inflammatory activity also in the joints of RA patients, we investigated: (i) the joint concentration of Hcy, and (ii) the effect of Hcy on cytokine production by unstimulated and IL-1beta-stimulated human RA cultured synoviocytes. METHODS: In 5 RA and 5 controls subjects, Hcy was measured in the blood and knee synovial fluid, and specimens of synovial tissue were taken to obtain cell cultures. Cultures were incubated with Hcy (10-100 micromol/l) +/- IL-1beta, and IL-6 and IL-8 concentrations were evaluated in the supernatants (ELISA) together with the activation of nuclear factor-kB (NF-kB) (immunocytochemistry). RESULTS: Hcy was present in synovial fluids, with a mean concentration significantly higher in RA patients than in controls (9.0 +/- 1.1 vs 5.9 +/- 1.2 micromol/l). Hcy enhanced IL-6 and IL-8 production in RA synoviocytes only (up to 35%). Moreover, Hcy produced a clear-cut activation of NF-kB in rheumatoid cells only. CONCLUSION: Hcy enhances IL-1-dependent cytokine production by rheumatoid synoviocytes at a concentration measurable in RA joints in vivo. Thus, in RA patients, Hcy may not only represent an important risk factor for the progression of cardiovascular diseases, but it may also contribute to the joint damage.
17543145 Differential association of HLA-DRB1 alleles in Japanese patients with early rheumatoid ar 2007 Mar OBJECTIVE: To evaluate the role of HLA-DRB1 genotypes and antibodies to cyclic citrullinated peptides (anti-CCP antibodies) in the development and radiographic progression of Japanese patients with rheumatoid arthritis (RA). METHODS: One hundred and ten patients with early RA (88 female, 22 male) who visited our clinic within 1 year of symptom onset were examined for anti-CCP antibody levels and HLA-DRB1 genotypes. HLA-DRB1 genotypes were also determined in 265 healthy controls. Radiographic progression over a 2-year interval was evaluated using the Larsen's method in 66 patients. RESULTS: Among the 110 patients with early RA, 82 patients (74.5%) were anti-CCP positive. Carrier frequency of HLA-DRB1*0405 was significantly increased in RA patients with anti-CCP antibodies compared with controls and RA patients without anti-CCP antibodies (odds ratio [OR] 3.4, 95% confidence interval [95% CI] 2.0-5.7 and OR 3.3, 95% CI 1.3-8.6, respectively). Carriership of one or two SE alleles was significantly associated with production of anti-CCP antibodies (OR 2.7, 95% CI 1.1-6.7 and OR 9.3, 95% CI 1.1-78.2, respectively). On the other hand, allele frequency of HLA-DRB1*0901 was significantly increased in RA patients without anti-CCP antibodies compared with controls and RA patients with anti-CCP antibodies (OR 2.2, 95% CI 1.1-4.1 and OR 3.0, 95% CI 1.4-6.4, respectively). CONCLUSION: In Japanese patients with RA, HLA-DRB1 SE alleles are associated with production of anti-CCP antibodies and HLA-DRB1 alleles appear to be differently associated with early RA depending on anti-CCP positivity as in Caucasian patients with RA.
18565243 Peripheral blood lymphocytes from patients with rheumatoid arthritis are differentially se 2008 Mar OBJECTIVE: The efficacy of anti-tumour necrosis factor-alpha (TNF-alpha) therapies in rheumatoid arthritis (RA) has been mainly attributed to TNF-alpha neutralisation. Other mechanism as immune cell apoptosis, which is impaired in RA, may also be induced by anti-TNF-alpha therapies. The aim of our study was to investigate whether TNF-alpha inhibitors could induce apoptosis in vitro of the peripheral blood lymphocytes of RA patients. METHODS: Peripheral blood mononuclear cells (PBMC) isolated from 24 patients with RA and 18 healthy donors were incubated with anti-TNF-alpha agents, infliximab or etanercept, in comparison with no agent and including an isotypic control, for 48 hours. Apoptosis was detected and quantified by annexin V labelling of phosphatidylserine externalization using cytofluorometric analysis and compared with PBMC production TNF-alpha in vitro. RESULTS: In healthy donors, induced apoptosis was observed in 0.3% to 3.8% of lymphocytes with both therapies. In RA patients the treatment induced lymphocyte apoptosis in 17 of 24 patients with a percentage of annexin V-positive lymphocytes ranging from 0.1% to 25%. Among these 17 RA patients, a significant in vitro lymphocyte apoptosis (> 4%) was observed in 11 patients (46%) compared with healthy donors (p < 0.01). The variability of the response to anti-TNF-alpha within the RA population was not dependent on TNF-alpha synthesis or disease activity. CONCLUSION: In vitro induction of lymphocyte apoptosis by anti-TNF-alpha was observed in a subgroup of RA patients. Based on these data, it would be of interest to further study the interindividual variations of sensitivity to apoptosis induced by TNF alpha inhibitors in relation to treatment efficacy or resistance observed in RA patients.