Mh van Rijswijk

Validity of single variables and composite indices for measuring disease activity in rheumatoid arthritis.

There is no agreement as to which variable best mirrors disease activity in rheumatoid arthritis (RA) and no studies have been performed on the validity of disease activity variables. In this study the validity of 10 commonly used single variables and three composite indices was tested. All patients participated in a large follow up study in two clinics. The patients (n = 233) had classical or definite RA and a disease duration of less than one year at entry. The mean follow up time was 30 months; the follow up frequency was once every four weeks; 6011 records were used in the analysis. The validation criteria included correlations with the other variables (correlational validity), with the physical disability (criterion validity I), and with the radiographically determined damage of hands and feet (construct validity). The judgment of a group of rheumatologists in clinical practice was also used as a model of criterion validity (II). In this comparison the disease activity score and Mallya index showed the best validity. The best single variable was the number of swollen joints. The validity of most single variables was poor and these variables were not suitable as single endpoint measures in clinical trials.

No increased mortality in patients with rheumatoid arthritis: up to 10 years of follow up from disease onset

OBJECTIVE To investigate mortality, functional capacity, and prognostic factors for mortality in an inception cohort of patients with recently diagnosed RA followed up for up to 10 years. METHODS The observed mortality of this inception cohort with recently diagnosed RA, was analysed in relation to the expected mortality, calculated with the aid of life tables of the general population of the Netherlands (matched for age and sex). Functional capacity was measured by the Health Assessment Questionnaire. Prognostic factors for mortality were analysed multivariately by the Cox proportional hazards model. RESULTS Between January 1985 and April 1997, 622 patients entered the study, and were included in the analysis of mortality. The death rate in the first 10 years of the disease was not significantly different from that of the general population. Fifty five patients from the study group died (16% up to 10 years of follow up). The most commonly reported causes of death were of cardiovascular and respiratory origin. The other causes of death could be classified into cancer, sepsis, amyloidosis, leukaemia, renal insufficiency of unknown cause, perforation of the oesophagus, probably related to the treatment with non-steroidal anti-inflammatory drugs, and pancytopenia during aurothioglucose treatment. Functional capacity improved significantly during the first six years compared with the value at start. Statistically significant predictors for death were age at the start and male sex. CONCLUSIONS In contrast with earlier studies performed, no excess mortality in the first 10 years of an inception cohort of patients with RA was seen. In addition, the functional capacity was relatively constant during the first six years after an initial improvement from baseline. Age at start and male sex were the only statistically significant predictors for death.

EFFECTS OF FISH OIL SUPPLEMENTATION IN RHEUMATOID-ARTHRITIS

Sixteen patients with rheumatoid arthritis entered a trial to determine the clinical and biochemical effects of dietary supplementation with fractionated fish oil fatty acids. A randomised, double blind, placebo controlled crossover design with 12 week treatment periods was used. Treatment with non-steroidal anti-inflammatory drugs and with disease modifying drugs was continued throughout the study. Placebo consisted of fractionated coconut oil. The following results favoured fish oil rather than placebo: joint swelling index and duration of early morning stiffness. Other clinical indices improved but did not reach statistical significance. During fish oil supplementation relative amounts of eicosapentaenoic acid and docosahexaenoic acid in the plasma cholesterol ester and neutrophil membrane phospholipid fractions increased, mainly at the expense of the omega-6 fatty acids. The mean neutrophil leucotriene B4 production in vitro showed a reduction after 12 weeks of fish oil supplementation. Leucotriene B5 production, which could not be detected either in the control or in the placebo period, rose to substantial quantities during fish oil treatment. This study shows that dietary fish oil supplementation is effective in suppressing clinical symptoms of rheumatoid arthritis.

WORK DISABILITY IN EARLY RHEUMATOID-ARTHRITIS

OBJECTIVE--To assess the impact of early rheumatoid arthritis (RA) on work status. METHODS--The employment status of 119 patients who had jobs before the onset of RA was examined. Patients with work disability were compared with those without, for several disease characteristics, therapeutic regimen, and educational level and age. RESULTS--Sixty two percent of the patients, particularly manual workers, reported some kind of work disability (7% worked less, 13% were on sick leave, and 42% had quit their jobs). Forty five patients (38%) stated that they were working without any restrictions; however, only 12 of this latter group (10% of the total group) had not encountered any changes at all within their jobs. The patients who reported work disability had a lower level of education and scored higher for several disease characteristics (erythrocyte sedimentation rate (ESR), joint tenderness, Health Assessment Questionnaire (HAQ), and Groningen Activity Restriction Scale) and were provided with more medication compared with patients without work disability, though only the educational level, disease duration, HAQ and ESR contributed significantly to work disability in logistic regression analysis. CONCLUSION--Even at an early stage, RA has a considerable impact on work status. This study indicates that work disability is dependent on disease characteristics and on the educational level of the patient.

Tumor necrosis factor (TNF) inhibits interleukin (IL)-1 and/or IL-6 stimulated synthesis of C-reactive protein (CRP) and serum amyloid A (SAA) in primary cultures of human hepatocytes

Interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) are considered as important mediators for the modulation of liver synthesis of acute phase proteins. However, studies of the direct effect of individual or a combination of these cytokines on the synthesis of acute phase proteins in human hepatocytes are still very limited. In this study, we have examined the synthesis of C-reactive protein (CRP) and serum amyloid A (SAA) in primary cultures of human hepatocytes exposed to recombinant(r)IL-1 alpha (100 U/ml), rIL-6 (2000 U/ml), rTNF alpha (30 U/ml) and to various combinations of these cytokines in the presence of 1 microM dexamethasone. Monoclonal antibodies to rTNF alpha and monospecific anti-rIL-6 sheep antiserum were also used to investigate the possible endogenous production of TNF or IL-6. The findings indicate: (1) IL-1 and IL-6 are stimulatory cytokines for the liver synthesis of CRP and SAA. Anti IL-6 abolishes the stimulatory effect of IL-1. These findings support the previous observation and indicate that IL-1 exerts its action on the enhanced synthesis of CRP and SAA at least in part via IL-6 production in the liver cell. (2) TNF is an inhibitory cytokine for the liver synthesis of CRP. It inhibits also the stimulatory effect of IL-1 and IL-6 on the synthesis of CRP and SAA. (3) Since anti-TNF enhances the stimulatory effect of IL-6 on the synthesis of CRP and SAA, it seems likely that TNF is also produced by the human hepatocytes. However, further studies for more direct evidence of the liver cell production of TNF, such as the detection of TNF messenger RNA are required.

Where has secondary amyloid gone

There is a growing clinical impression that the incidence of amyloid secondary to rheumatoid disease is declining. Recent studies from Finland strongly support this impression.1-3 The prevalence of amyloidosis in patients with rheumatoid arthritis who died in 1989 (about 6%)1 was lower than in earlier studies.4 In a recent cohort of patients with early rheumatoid arthritis followed up for 8–14 years no one died from amyloidosis.2 In a hospital for rheumatic diseases the annual number of biopsies positive for amyloid decreased from more than 60 in 1987 to fewer than 10 recently.3 The question arises whether this is a true decline of the incidence or a more concealed clinical presentation of this type of amyloidosis. Secondary amyloidosis is nowadays called systemic AA amyloidosis. It is associated with chronic inflammation and results from systemic deposition of the acute phase reactant serum amyloid A protein (SAA) in a fibrillar structure. SAA behaves similarly to C reactive protein, being hardly detectable in normal situations and increasing quickly and dramatically during inflammation.5 In selected populations of patients with rheumatoid arthritis 5–20% of patients with longstanding disease will develop AA amyloidosis, depending upon the severity and duration of the arthritis in the population investigated.6 7 Although longstanding inflammation is necessary for the development of AA amyloidosis, it is not sufficient. Most people with a longstanding increase in SAA levels will never develop AA amyloidosis. In Europe AA amyloidosis is seen more often than in North America. Food, lifestyle, differences in drug treatment, other concurrent diseases, and genetic factors might be responsible for this difference. Genetic predisposition may be conditional for amyloid formation. One possible factor is homozygosity for SAA subtypes.8 9 Genetic research of diseases connected to the development of AA amyloidosis, such as familial Mediterranean fever, …

IgM, IgA and IgG rheumatoid factors in early rheumatoid arthritis. Predictive of radiological progression?

The significance of IgM, IgA and IgG rheumatoid factors (RF) for the prediction of radiological progression, and as process variables during follow-up, was evaluated in a three-year prospective study of 149 patients with early rheumatoid arthritis (symptoms < 1 year at study entry). The occurrence of IgA-RF and IgG-RF at study entry without simultaneous occurrence of IgM-RF, and the seroconversion from RF-negative at entry to RF-positive during follow-up appeared to be unusual. A significant correlation was found between each of the RF-isotype levels at entry and radiological progression after three years. However, no significant prognostic value of IgA-RF and IgG-RF could be demonstrated if analysed in combination with IgM-RF, initial disease activity (as measured by C-reactive protein level), initial radiologic score, HLA-DR4 and HLA-DR2. Although IgM-RF levels generally reflected the course of disease activity and did so better than IgA-RF and IgG-RF levels, their clinical significance as process variables appeared to be limited compared to C-reactive protein.

Interleukin-6 in relation to other proinflammatory cytokines, chemotactic activity and neutrophil activation in rheumatoid synovial fluid.

OBJECTIVE--To evaluate the relation between synovial fluid (SF) concentrations of interleukin-6 (IL-6) and other mediators of inflammation which are responsible for joint degradation in rheumatoid arthritis (RA). METHODS--We measured IL-6, IL-1 beta, tumour necrosis factor alpha (TNF alpha), granulocyte macrophage colony stimulating factor, IL-8, and polymorphonuclear leucocyte (PMNL) chemotaxis and degranulation in SF from patients with RA (n = 30) in the early phase of the disease. RESULTS--In a cross-sectional study IL-6 concentrations correlated with those of IL-1 beta, IL-8 and with PMNL activation as reflected by lactoferrin concentrations. In a longitudinal study, changes in IL-6 concentrations correlated with changes in TNF alpha, IL-8 and lactoferrin concentrations. CONCLUSION--IL-6 in SF appears to reflect the local proinflammatory, potentially erosive activity in RA. This supports the use of acute phase proteins, which are mainly induced by IL-6, as variables to monitor the course of RA.

A quantitative method for detecting deposits of amyloid A protein in aspirated fat tissue of patients with arthritis

OBJECTIVE To describe a new, quantitative, and reproducible method for detecting deposits of amyloid A protein in aspirated fat tissue and to compare it with smears stained with Congo red. METHODS After extraction of at least 30 mg of abdominal fat tissue in guanidine, the amyloid A protein concentration was measured by a monoclonal antibody-based sandwich ELISA. RESULTS The concentrations in 24 patients with arthritis and AA amyloidosis (median 236, range 1.1–8530 ng/mg tissue) were higher (p<0.001) than in non-arthritic controls, uncomplicated rheumatoid arthritis, and other types of systemic amyloidosis (median 1.1, range 1.1–11.6 ng/mg tissue). Patients with extensive deposits, according to Congo red staining, had higher concentrations than patients with minute deposits. CONCLUSION This is a new, quantitative, and reproducible method for detecting deposits of amyloid A protein in aspirated fat tissue of patients with arthritis, even when minute deposits are present as detected in smears stained with Congo red.

Clinical significance of interleukin-6 measurement in early rheumatoid arthritis: relation with laboratory and clinical variables and radiological progression in a three year prospective study.

OBJECTIVE--To evaluate the clinical significance of interleukin-6 (IL-6) measurements in relation to laboratory and clinical measures of disease activity and radiological progression in early rheumatoid arthritis (RA). METHODS--A prospective study was performed in 51 patients with early RA during the first three years of the disease, with monthly clinical and laboratory assessments and biannual radiographs of the hands and feet. IL-6 was measured by enzyme linked immunosorbent assay (ELISA). Cross sectional (n = 51) and longitudinal (n = 20) correlations between plasma IL-6 concentrations and values of C reactive protein (CRP), serum amyloid A protein (SAA), erythrocyte sedimentation rate (ESR), haemoglobin (Hb), platelets, and joint scores were calculated, and correlations made between time integrated values of IL-6, CRP and ESR, and radiological progression over three years (n = 20). RESULTS--Significant correlations were found between IL-6 and the acute phase response and platelets, but variable results were obtained for the correlation between IL-6 and Hb. In contrast to a significant correlation between time integrated values of CRP or ESR and radiological progression, time integrated values of IL-6 did not correlate with radiological progression over three years follow up. CONCLUSION--The course of disease activity and the radiological progression of joint damage are better reflected by CRP, SAA, and ESR values than by plasma IL-6 concentrations, particularly in stages of low disease activity.