Biomedical subjects
Publications and source records attributed to R van Vollenhoven.
Data from several different monitoring systems are examined. The potential for registers based on data obtained from clinical practice, and linkage of such data to national health and population registers, is discussed. The approach described is a possible prototype for long term surveillance systems needed for the safe introduction of new treatments.
OBJECTIVE: When one TNFalpha blocker (etanercept or infliximab) has failed, to determine whether it makes sense to treat patients with the other. PATIENTS AND METHODS: Since 1999 patients treated with etanercept or infliximab have been systematically followed up at our institution in the STURE database. We identified 31 patients who had received both agents. RESULTS: Eighteen patients received etanercept first; discontinuation was mostly due to lack of efficacy. DAS28 values had improved only slightly with etanercept, with a mean (SEM) best DAS28 value of 4.8 (0.6). After switching to infliximab, the mean best DAS28 was 3.6 (0.6)-significantly better than the previous result (p<0.05). Similarly, the mean best ACR-N during etanercept treatment was 17.2 (6.65) and during subsequent infliximab treatment 40.4 (10.6) (p = 0.08). Thirteen patients received infliximab first; discontinuation was mainly due to adverse events. The best DAS28 value achieved during etanercept was 3.6 (0.4) compared with 4.1 (0.4) for infliximab (p<0.05), but the change in DAS28 was not different and ACR-N were similar for infliximab and etanercept in this group. CONCLUSION: For patients with insufficient efficacy from etanercept, treatment with infliximab provided better results, suggesting that a trial of infliximab is reasonable for such patients. For patients who discontinued infliximab owing to adverse events, treatment with etanercept gave at least similar clinical efficacy. Taken together, these data provide support for a trial of the reciprocal TNFalpha blocker in patients when one such agent has failed.
TNF-alpha is a proinflammatory cytokine. It has a key function in the inflammatory cascade both systemically and locally in the inflamed joints of patients affected by rheumatoid arthritis (RA). Treatment with two different "biological" drugs that block the proinflammatory capacity of TNF-alpha has recently been approved by the European drug authorities. This paper discusses experience gained in clinical trials and during the first year of treatment in Sweden using infliximab (anti-TNF-alpha monoclonal antibodies) and etanercept (recombinant TNF-alpha receptor fusion protein).
OBJECTIVE: Peripheral T cells from patients with rheumatoid arthritis (RA) are hyporesponsive when stimulated with antigen or mitogen in vitro, possibly owing to increased production of proinflammatory cytokines such as tumour necrosis factor alpha (TNFalpha). This study sought to find out if and how RA T cell reactivity is affected during treatment with etanercept (Enbrel), a soluble TNFalpha receptor. METHODS: Heparinised blood was collected from patients with RA at baseline, after four and eight weeks of etanercept treatment, and from healthy controls. After density separation spontaneous production of interferon gamma (IFNgamma), TNFalpha, interleukin 6 (IL6), and IL10 by peripheral blood mononuclear cells (PBMC) was detected by ELISPOT. For detection of T cell reactivity, PBMC were stimulated in vitro with mitogen (phytohaemagglutinin (PHA)), microbial antigens (purified protein derivative (PPD), influenza), or an autoantigen, collagen type II (CII). Supernatants were analysed for IFNgamma and IL2 content by enzyme linked immunosorbent assay (ELISA). RESULTS: In RA the number of cells spontaneously producing IFNgamma was significantly increased after four, but not eight weeks' treatment with etanercept. T cell reactivity, as measured by IFNgamma production to PPD, influenza, and CII was significantly increased after four and sustained after eight weeks' treatment, whereas IFNgamma production induced by PHA remained unchanged. TNFalpha production was significantly higher in patients with RA than in controls and did not change during etanercept treatment. CONCLUSION: Treatment of patients with RA with etanercept may lead to increased peripheral T cell reactivity both to microbial antigens and to self antigens such as CII. These findings indicate that TNFalpha blockade may not only suppress but also stimulate certain aspects of antimicrobial immune defence and autoimmunity.
OBJECTIVE: To investigate systemic and intrathecal production of proinflammatory cytokines in relation to cerebrospinal fluid (CSF) nitric oxide (NO) release in patients with neuropsychiatric lupus erythematosus (NPLE). METHODS: Thirty patients with NPLE rated as mild, moderate, or severe were studied and CSF was obtained from 21 of these. Cytokine mRNA expressing cells were detected by in situ hybridisation. Soluble cytokines were assessed by enzyme linked immunosorbent assay (ELISA). Nitrite and nitrate were determined by capillary electrophoresis. RESULTS: Patients with NPLE had high numbers of lymphocytes expressing mRNA for tumour necrosis factor alpha (TNFalpha), interferon gamma, and interleukin 10 in blood. The number of peripheral blood TNFalpha mRNA positive cells correlated strongly with the level of NO metabolites in the CSF (r(2)=0.69). Both the number of peripheral blood mononuclear cells expressing mRNA for TNFalpha as well as the CSF level of NO metabolites correlated with NPLE disease severity. CONCLUSION: These data suggest that increased peripheral production of proinflammatory cytokines such as TNFalpha may contribute both to an increased production of NO in the central nervous system and to generation of clinical NPLE. The data also support the possibility that measurements of NO metabolites in CSF may be of value in the diagnosis of neurological symptoms related to SLE.
OBJECTIVE: Modifiable psychosocial factors that are associated with health outcomes may provide new opportunities for treatment. We investigated the associations of various psychosocial factors with 3 measures of morbidity in women with systemic lupus erythematosus (SLE). METHODS: We collected information on 16 social, psychological, behavioral, and medical care factors in a cross sectional survey of 100 women with SLE, and related these to measures of physical disability (assessed by the Health Assessment Questionnaire Disability Index), SLE activity (assessed by the Systemic Lupus Activity Measure), and cumulative organ damage (assessed by the SLICC/ACR Damage Index). RESULTS: In multivariate analyses, greater physical disability was significantly associated with higher depression scale scores and higher body mass indexes. Greater SLE activity was associated with less adequate social support. Greater cumulative organ damage was associated with lower self-esteem and a time orientation that favored the present over the future. Financial barriers to medical care, knowledge about SLE, health locus of control, marital status, and health behaviors including compliance with medications, smoking, alcohol use, and exercise, were not significantly associated with any measure of morbidity. CONCLUSION: Selected psychosocial factors are associated with morbidity in SLE, but differ with the measure of morbidity examined.
OBJECTIVE: Health outcomes of patients with chronic illnesses are commonly worse in people of lower socioeconomic status (SES). We investigated psychosocial factors that may mediate the relationship between SES and measures of morbidity in women with systemic lupus erythematosus (SLE). METHODS: We collected information on SES, psychosocial factors, and health status in a cross sectional survey of 100 women with SLE. SES was rated using the Hollingshead Two-Factor Index, a weighted average of years of formal education and occupational prestige (higher Hollingshead Index=lower SES). Health status measures included the Health Assessment Questionnaire Disability Index (HAQ), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR), the Systemic Lupus Activity Measure (SLAM), and the SLE Disease Activity Index (SLEDAI). Potential mediators consisted of 18 environmental, medical care, social, psychological, and behavioral factors. RESULTS: Patients with higher Hollingshead Indexes (lower SES) had more functional disability as measured by the HAQ (r=0.22: p=0.03) and more cumulative organ damage as measured by the SLICC/ACR Damage Index (r = 0.19; p=0.06). SES was not related to either the SLAM or SLEDAI. Significant univariate associations were present between the Hollingshead Index and 10 potential mediating variables: household crowding, insurance status, organizational barriers to medical care, depression, health locus of control by powerful others, SLE knowledge, social support, marital status, body mass index, and regular alcohol use. However, in multiple linear regression analyses, only 3 of these variables modified the relationship between Hollingshead Index and the HAQ: more severe depression scores, higher body mass index, and more restricted access to medical care. More severe depression and greater locus of control by powerful others tended to mediate the relationship between low SES and greater organ damage. CONCLUSION: SES is related to morbidity in women with SLE. There are identifiable and potentially modifiable mediators of this relationship.
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CD4+ T cells lacking the costimulatory molecule CD28 have been described both in elderly individuals and in chronic inflammatory disorders, one being rheumatoid arthritis (RA). We, in this study, provide a comprehensive characterization of cell surface markers on and function of such CD28nullCD4+ T cells, as well as correlations with clinical parameters. We conclude that of all surface markers associated with these cells, only CD57 and CD11b are expressed on the majority of them. This CD28null population occurred in one-third of patients with RA and was independent of clinical characteristics. The population was persistent and expanded in peripheral blood, but was excluded from the joint in most patients. Functionally, CD28nullCD4+ T cells were potent effector memory cells with regard to their proliferation and cytokine-secretion profiles. This capacity correlated with a hitherto unpublished surface phenotype, the cells being uniformly CCR7- and CD43high. Moreover, a new terminally differentiated CD45RA+CCR7- population of CD4+ T cells was identified. We would like to suggest that in the unbalanced immune system of patients with autoimmune disease and chronic infection an expanded CD28nullCD4+ T-cell population able to secrete high levels of cytokines is likely to contribute to disease manifestations.