Utility and direct costs: ankylosing spondylitis compared with rheumatoid arthritis.

OBJECTIVES: To compare utility and disease-specific direct costs between patients with ankylosing spondylitis (AS) and patients with rheumatoid arthritis (RA) in the Netherlands. METHODS: Patients with AS and those with RA completed questions on disease characteristics, the EuroQol-5D (EQ-5D) to assess utility, and questionnaire resource utilisation. Resource utilisation was assessed prospectively in AS, but retrospectively in RA. True cost estimates (2003) were used to calculate the costs. Differences in disease characteristics between AS and RA were described, and determinants of EQ-5D utility and costs were explored by Cox proportional hazard regressions. RESULTS: 576 patients with RA and 132 with AS completed the questionnaires. EQ-5D utility (0.63 vs 0.7) was lower, and annual direct costs higher in RA (euro5167 vs euro2574). In multivariate Cox proportional hazard regressions, there was no difference in utility between the diagnostic groups, but patients with RA incurred higher direct costs after controlling for age, gender and disease duration. CONCLUSIONS: In patients with RA and patients with AS, who are under the care of a rheumatologist, utility is equally reduced, but healthcare costs are higher in RA after controlling for age, gender and disease duration. These data can be helpful to provide insights into the differences and similarities between the healthcare needs of both patient groups and to identify issues for further research and for policy in healthcare organisations.

Interleukin 10 (IL-10), not IL-4 or interferon-gamma production, correlates with progression of joint destruction in rheumatoid arthritis.

OBJECTIVE: Both interleukin 4 (IL-4) and IL-10, separately and in combination, and under in vitro and in vivo conditions in animals, have been reported to inhibit characteristics of rheumatoid arthritis (RA) and experimentally induced arthritis. We investigated if IL-10 and IL-4 production, as well as interferon-gamma (IFN-gamma) production, opposing IL-4, were related to RA disease variables. A method was chosen to exclude the influence of age and disease duration. METHODS: We selected RA patients with mild and severe disease. Inclusion criteria were erythrocyte sedimentation rate (ESR) < or = 28 mm/h and > or = 50, C-reactive protein (CRP) < or = 20 and > or = 30, Thompson joint score < or = 60 and > or = 100 and radiographic joint damage score, Sharp score < or = 30 and > or = 40. Age and disease duration were restricted: 30 to 70 years and 5 to 15 years, respectively. Peripheral blood mononuclear cells were isolated and the ex vivo 48 h production of T cell IL-10, IL-4, and IFN-gamma (after CD3-CD28 stimulation) was assessed and was correlated to clinical variables. RESULTS: Only IL-10 production differed significantly between the 2 groups of RA patients, being highest in the "mild" group. Taking all patients together, a strong negative correlation was found between IL-10 production and radiographic joint damage (r = -0.53, p < 0.001) as well as progression of joint damage (r = -0.56, p < 0.0001). Similar negative correlations, although less powerful, were found between IL-10 production and ESR, CRP, and Thompson joint score. No correlation was found for IFN-gamma, IL-4, or the ratio of the 2 with disease activity variables or joint damage. CONCLUSION: The findings suggest that the high IL-10 production found in patients with RA may be protective, especially against progression of joint destruction in RA.

Lymphocyte stimulation by CD3-CD28 enables detection of low T cell interferon-gamma and interleukin-4 production in rheumatoid arthritis.

The analysis of cytokine production is increasingly important in defining the course of an immune response and in evaluating specific therapies of immune diseases. In rheumatoid arthritis (RA), a dysregulation in T1/T2 cell balance, as defined by the production of their specific cytokines, IFN-gamma and IL-4, respectively, is suggested. A predominance of T1-cell mediated macrophage activity in the joint plays a key role in the destruction of articular cartilage and subchondral bone, whereas local T2 cell activity, mitigating disease, fails. However, analysis of the cytokines defining both T cell subsets is difficult and spontaneous production is often below detection limits. Several stimuli are therefore used to increase cytokine production. In the present study we examined whether stimulation of peripheral blood T cells in the context of mononuclear cells (PB MNC) by CD3-CD28 is a reliable method for assessing IFN-gamma and IL-4 production and is representative for the spontaneous production of these cytokines. The production of IFN-gamma and IL-4 following CD3-CD28 stimulation of RA PB MNC correlated significantly in a ratio 1 : 1 with production following ionomycin-PMA stimulation. In samples with detectable spontaneous production of IFNgamma and IL-4, production following CD3-CD28 stimulation was significantly higher than in stimulated samples with undetectable spontaneous production. Moreover, in the case of spontaneous production there was a significant positive linear correlation between the CD3-CD28 stimulated and spontaneous IFNgamma and IL-4 production, although production of both cytokines was not equally enhanced. Serial sampling did not show significant daily or weekly variation in stimulated cytokine production. The results demonstrate that a pecific T-cell stimulation by CD3-CD28 is a reliable way to enhance IFN-gamma and IL-4 production above the detection limit and so measure the T1/T2 cell balance in RA.

The immune suppressive effect of dexamethasone in rheumatoid arthritis is accompanied by upregulation of interleukin 10 and by differential changes in interferon gamma and interleukin 4 production.

OBJECTIVES: The influence of dexamethasone on interleukin 10 (IL10) production and the type 1 (T1)/type 2 (T2) T cell balance found in rheumatoid arthritis (RA) was studied. METHODS: Peripheral blood mononuclear cells (PB MNC) were isolated from 14 RA patients both before and 7 and 42 days after high dose dexamethasone pulse therapy. The ex vivo production of IL10, interferon gamma (IFN gamma) (T1 cell), and IL4 (T2 cell) by PB MNCs was assessed, along with parameters of disease activity (erythrocyte sedimentation rate, C reactive protein, Visual Analogue Scale, Thompson joint score). In addition, the in vitro effect of dexamethasone (0.02, 0.2, and 2 microM) on PB MNC IL10, IFN gamma, and IL4 production was studied. RESULTS: Dexamethasone pulse therapy resulted in a rapid and sustained decrease in RA disease activity. IL10 production increased after dexamethasone treatment and this was sustained for at least six weeks. A transient strong decrease in IFN gamma was seen shortly after corticosteroid treatment, while IL4 only decreased slightly. This led to an increased IL-4/IFN gamma ratio. In vitro, IL10 production was not detectable, IFN gamma and IL4 decreased, but the effect was more pronounced for IFN gamma than for IL4, which again resulted in an increased IL4/IFN gamma ratio. CONCLUSION: Dexamethasone therapy in RA patients leads to a rapid, clinically beneficial effect. The upregulation of IL10 production may be involved in the prolonged clinical benefit. The strong immunosuppressive effect is most evident in the decrease in IFN gamma, and is therefore accompanied by a relative shift towards T2 cell activity. In vitro evaluation showed that this shift in T cell balance was a direct effect of dexamethasone and thus independent of the hypothalamic-pituitary-adrenal axis.

Mutual antagonism of rheumatoid arthritis and hay fever; a role for type 1/type 2 T cell balance.

OBJECTIVES: The balance between interferon gamma (IFN gamma) and interleukin 4 (IL4) producing T cells (T1 and T2 cells) seems to be of importance in many (auto)immune disorders. In general, T1 cell activity is important in cellular immunity whereas T2 cell activity plays a part in humoral responses. T1 cell activity predominates in joints of patients with rheumatoid arthritis (RA) whereas T2 cell activity is characteristic of atopic syndromes. This study investigated whether the prevalence of hay fever in RA is low and if severity of RA (T1 cell activity) can be influenced by the concomitant occurrence of a T2 cell mediated disease (hay fever). METHODS: The prevalence of hay fever was assessed in 643 consecutive (RA and non-RA) patients seen in our outpatient clinic and confirmed by skin test and specific IgE. Of this group the 12 RA patients with hay fever were compared with RA patients without hay fever (matched for age, sex, and disease duration). RESULTS: The prevalence of hay fever in RA patients is lower than in non-RA patients (4% versus 8%), and yields a relative risk for RA patients to develop hay fever of 0.48. RA patients with hay fever showed a lower disease activity (erythrocyte sedimentation rate, C reactive protein, Thompson joint score, and radiographic joint damage (Sharp) score) than RA patients without hay fever. The clinical data were related to peripheral blood T1/T2 cell balance: a lower IFN gamma/IL4 ratio was observed for RA patients with hay fever, indicating a comparatively increased T2 cell activity in RA patients with hay fever. CONCLUSION: These results argue in favour of the exploration of treatments aimed at regulation of a possible imbalance in T1/T2 cell activity in RA.

Decrease in peripheral type 1 over type 2 T cell cytokine production in patients with rheumatoid arthritis correlates with an increase in severity of disease.

OBJECTIVES: To compare peripheral type 1 (T1) and type 2 (T2) T cell activities in rheumatoid arthritis (RA) patients with that found for osteoarthritic (OA) patients and healthy controls and to correlate peripheral T1/T2 cell activity in RA with parameters of the disease. METHODS: Peripheral blood mononuclear cells were isolated from patients with RA (n = 66), OA (n = 19), and healthy controls (n = 15). Primary T cell activity in these mononuclear cells was enhanced by means of anti-CD3/anti-CD28, which mimicks stimulation of T cells by activation of the T cell receptor and a major co-stimulatory signal. Interferon gamma (IFN gamma) production and interleukin 4 (IL4) production in the three groups were quantified as measures of T1 and T2 cell activity, respectively, and compared. Serum tumour necrosis factor alpha (TNF alpha), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and joint destruction assessed radiographically of RA patients were determined as parameters of disease activity and correlated with T1/T2 cell activity. RESULTS: Peripheral T cells from RA patients produced significantly less IFN gamma and more IL4 than T cells from both age and sex matched OA patients and healthy controls. Moreover, in RA patients both a decrease in IFN gamma and an increase in IL4 production correlated with an increase in serum TNF alpha, ESR, CRP, and joint destruction. CONCLUSIONS: These results suggest a role for differential T cell activity in RA. In view of the intra-articular T1 cell predominance the results might be explained by selective T1 cell migration into the joint or peripheral suppression of T1 cell activity.