Relation between body mass index and radiological progression in patients with rheumatoid arthritis

OBJECTIVE: To determine if there is an influence of body mass index (BMI) on the radiological progression in early and longer duration rheumatoid arthritis (RA). METHODS: Fifty-four patients with RA were observed in a progressive 2 year followup for radiological progression of joint damage. At the beginning of study, 27 (50%) patients had a duration of complaints less than 6 months, grouped as early RA. BMI at the beginning and end of the study were monitored, together with HLA-DRB1 alleles, initial joint erosions, duration of disease, age, sex, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Outcome was defined as radiographic damage according to yearly increase of Larsen score. RESULTS: Increased radiographic joint damage of patients was significantly correlated with lower BMI at the beginning of the study (r = 0.363, p < 0.05), the presence of initial joint erosions (r = 0.341, p < 0.01), ESR (r = 0.315, p < 0.05), and CRP at study entry (r = 0.427, p < 0.01). Patients with an increase of Larsen score > or = 5.8/year were found to have a lower weight at the beginning of their complaints (BMI 24.8 +/- 4.7 vs 27.8 +/- 3.8; p < 0.05) as well as after the time of observation (BMI 24.6 +/- 3.7 vs 27.6 +/- 4.9; p < 0.05). Stepwise logistic regression analysis revealed a BMI < 27 at the beginning of disease (beta = 2.04, p = 0.003, odds ratio = 7.69), the presence of HLA-DR4 shared epitope (beta = 1.76, p = 0.015, OR 5.82), and joint erosions at study entry (beta = 1.56, p = 0.044, OR 4.78) as significant predictors for rapid joint damage. CONCLUSION: Together with the presence of HLA-DR4 shared epitope and erosive disease at study entry, a low BMI at the beginning of RA was found in association with higher radiographic progression in RA. Accordingly, BMI could be of interest as a sensitive and inflammation-independent predictor for radiological outcome of RA.     

Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial

OBJECTIVE: To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX. METHODS: Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54. RESULTS: C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX-only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (> or = 3 mg/dl) and ESR (> or = 52 mm/hour) tertiles in the MTX-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS > or = 10.5) showed less progression with infliximab plus MTX compared with MTX alone (-0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab. CONCLUSION: High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.     

Serum pro-matrix metalloproteinase-3 as an indicator of disease activity and severity in rheumatoid arthritis: comparison with traditional markers

Matrix metalloproteinase-3 (MMP-3) production increases in rheumatoid arthritis (RA) and has been proposed as a marker of disease activity and joint damage. The aim of this cross-sectional study is to examine the usefulness of serum proMMP-3 as an indicator of disease activity and severity in comparison with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Serum proMMP-3 was measured by a quantitative ELISA in 85 RA patients and 70 healthy subjects. Clinical and laboratory measures of disease activity and severity were obtained. Radiological joint damage was assessed by the method of Larsen. Serum proMMP-3 was significantly higher in RA patients than that in the healthy subjects. The active RA patients had significantly higher serum proMMP-3 than the inactive patients. Serum proMMP-3 was significantly correlated with some parameters of disease activity including swollen joints count, proximal interphalangeal joint score, morning stiffness, and Health Assessment Questionnaire; however, ESR and serum CRP were better correlated with all indicators of the disease activity than proMMP-3. The analysis of receiver operating characteristic supported that ESR and CRP had higher performance for reflection of activity compared to proMMP-3. There were no significant associations among Larsen score and proMMP-3, ESR, and CRP. Our results suggest that the cross-sectional measurement of serum proMMP-3 could not give additional information about RA disease activity compared to ESR and CRP, and could not give any information about joint damage.     

Relation of plasma dexamethasone to clinical response.

OBJECTIVE: The clinical effects of high dosage pulse glucocorticosteroid (GS) infusion as a treatment for rheumatoid arthritis (RA) differ considerably between patients. The aim of the present study was to gain more insight into these differences in clinical response. METHODS: Twenty-three RA patients (6 M/17 F) with treatment-resistant active erosive disease were treated with GS pulse therapy, consisting of 3 infusions of 200 mg dexamethasone at 3-day intervals. Plasma dexamethasone and plasma cortisol levels, as well as the mononuclear cell glucocorticosteroid receptor density, were determined on days 0, 2, 6, 12 and 40 after the start of therapy. Clinical evaluation consisted of the Thompson articular index, the erythrocyte sedimentation rate (ESR), and the serum concentration of C reactive protein (CRP). RESULTS: Plasma dexamethasone levels in RA patients determined during pulse therapy revealed the existence of two groups. One group reached significantly (p < 0.05) higher plasma levels than another group comparable for age and sex. The CRP, ESR and Thompson joint score prior to the start of pulse therapy were all higher (p < 0.05) for the high plasma dexamethasone group. The decrease in ESR, CRP and the Thompson joint score was also significantly greater (all p < 0.05) for the high plasma dexamethasone group. Plasma cortisol, as well as the GS receptor density at the start of treatment, did not differ between the two groups; both decreased after the first pulse in both groups and returned to pre-treatment values shortly after the last infusion. CONCLUSION: The treatment of refractory RA with dexamethasone pulse therapy is, on average, beneficial. The high plasma dexamethasone levels reached might depend on the greater severity of the disease in these patients prior to the start of the treatment, and result in greater changes in the disease parameters. Glucocorticosteroid receptor density measurements made during and directly after high dose pulse dexamethasone treatment proved to be unreliable because of the high plasma dexamethasone levels.     

Rheumatoid factor measured by fluoroimmunoassay: a responsive measure of rheumatoid arthritis disease activity that is associated with joint damage

OBJECTIVES: To determine whether rheumatoid factors (RFs), measured as continuous variables by time resolved fluoroimmunoassay, reflect disease activity in rheumatoid arthritis (RA). Further, to study the association of RFs and other disease activity parameters with radiological joint damage, especially in individual patients. METHODS: In active, early RA, IgM and IgA RFs, as well as erythrocyte sedimentation rate (ESR), C reactive protein (CRP), tender joint score, and swollen joint score were assessed regularly. At the study start and at 56 and 80 weeks, radiographs of hands and feet were assessed by the Sharp score (van der Heijde modification). Associations between RFs and disease activity parameters were studied. In addition, associations between radiographic damage and disease activity parameters (baseline and time integrated) were analysed by non-parametric tests and multiple regression analysis. The relation between time integrated disease activity parameters and radiological damage in individual patients was analysed and visualised. RESULTS: 155 patients were included. RF levels were strongly associated with the disease activity parameters (especially ESR and CRP) and with each other. All disease activity parameters, at baseline as well as time integrated parameters, were associated with (the progression of) radiographic damage. Moreover, in individual patients, a linear relationship between time integrated disease activity parameters and progression of radiological damage was seen. CONCLUSION: RFs, measured as continuous variables, can be considered as disease activity parameters in patients with RA. The level of RF at baseline and the exposure to RF over time is associated with radiological damage. In individual patients, there is a constant relation between disease activity and radiological damage.     

Calprotectin (a major leucocyte protein) is strongly and independently correlated with joint inflammation and damage in rheumatoid arthritis

OBJECTIVE: Calprotectin is a major leucocyte protein, shown to correlate well with laboratory and clinical assessments in several inflammatory rheumatic diseases, and large concentrations of calprotectin have been found in synovial fluid from patients with rheumatoid arthritis (RA). The objective of the present study was to examine correlations between calprotectin and joint damage. METHODS: 145 patients with RA were analysed cross sectionally with laboratory (calprotectin, C reactive protein (CRP), and erythrocyte sedimentation rate (ESR)), clinical (28 joint counts (tender, swollen), physician global VAS, DAS28 and RA Articular Damage score (RAAD)), and radiographic (plain hand radiographs; modified Sharp's method) measurements, on the same day. RESULTS: Calprotectin showed a highly significant correlation with measures of joint damage; modified Sharp score r = 0.43 (p<0.001) and RAAD r = 0.40 (p<0.001). The association with modified Sharp score and RAAD score was maintained after adjustment for CRP, ESR, rheumatoid factor, DAS28, sex, and age in a multiple regression analysis (p = 0.018 and p = 0.04, respectively), while neither CRP nor ESR showed any independent associations. Highly significant correlations (p<0.001) were also found between calprotectin and both laboratory and clinical markers of inflammation. CONCLUSION: Calprotectin was found to significantly and independently explain the variation in the radiological and clinical assessments of joint damage. Longitudinal studies are required to examine whether calprotectin may predict the progression of joint damage in RA.     

Serum matrix metalloproteinase 3 levels in comparison to C-reactive protein in periods with and without progression of radiological damage in patients with early rheumatoid arthritis

OBJECTIVE: To evaluate serum matrix metalloproteinase 3 (MMP-3) levels in comparison to C-reactive protein (CRP) in periods with and without progression of radiological damage in patients with early rheumatoid arthritis (RA). METHODS: Thirty-two patients with RA and radiological progression (> or = 5 points according to the Sharp/van der Heijde method) during 6 months followed by a 6-month period without radiological progression (< or = 1 point) were selected from a prospective follow-up study of early RA patients. Serum MMP-3 levels, CRP, the erythrocyte sedimentation rate (ESR), disease activity index (DAS), swollen joint count (SJC), tender joint count (TJC), and Ritchie articular index (RAI) were measured monthly and results were transformed into mean values for the 6-month periods. RESULTS: During the period with radiological progression the mean serum MMP-3 correlated significantly with the mean CRP (r = 0.68, p < 0.001), ESR (r = 0.54, p = 0.001) and swollen joint count (r = 0.48, p = 0.006). In the period without radiological progression the mean serum MMP-3 only correlated with the mean CRP (r = 0.44, p = 0.012). Individual changes--expressed in percentages (%)--between the two periods showed a decrease in both the mean serum MMP-3 and CRP in 19 and an increase in 3 patients, in parallel with other markers of disease activity in these patients (69% of cases). The individual change (%) in mean serum MMP-3 or CRP did not correlate with the difference in radiological progression between the two periods. CONCLUSIONS: Serum MMP-3 and CRP are closely related and there seems to be no difference between serum MMP-3 and CRP with regard to the monitoring of the progression of radiological damage.     

Different monocyte reaction patterns in newly diagnosed,untreated rheumatoid arthritis and lupus patients probably confer disparate C-reactive protein levels

OBJECTIVES: To investigate the different capacities of monocytes to produce cytokines in newly diagnosed, untreated patients with rheumatoid arthritis (RA) or systemic lupus and to examine the possible correlation among serum C-reactive protein (CRP), cytokines, swollen joint counts, and erythrocyte sedimentation rates (ESR) in untreated RA patients. METHODS: Monocytes from untreated RA or lupus patients were cultured in vitro with lipopolysaccharide (LPS, as bacterial infection) or immune complexes (as endogenous immune deviation) and supernatants were collected for cytokine determination. Sera from RA patients were assayed for interleukin-6 (IL-6), IL-1 beta, IL-10, tumor necrosis factor-alpha (TNF-alpha) and IL-1 receptor antagonist (IL-1ra). These cytokines were related to serum CRP, swollen joint counts, and ESR. RESULTS: RA monocytes uniformly produced IL-6, IL-1 beta, TNF-alpha, or IL-10 in vitro. In contrast, lupus monocytes could be divided into two subsets: (i) monocytes which produce cytokines on LPS stimulation but not on challenging with immune complexes; and (ii) monocytes which, interestingly, generate cytokines on stimulation by immune complexes but not LPS. These cytokines in turn stimulate the liver to synthesize CRP differently in the SLE subsets and RA patients. Moreover, serum IL-1ra levels correlated significantly with serum IL-6, IL-1 beta, and TNF-alpha concentrations (p = 0.005, 0.008, or 0.040, respectively), but not with IL-10 (p = 0.582) in RA patients. CONCLUSIONS: Two lupus subsets exist that react either to LPS or immune complexes to produce CRP-inducing cytokines, in contrast to homogeneous RA monocytes. This is the first report that different reaction patterns of CRP-inducing cytokine production in RA and lupus monocytes probably underlie the high CRP levels in RA versus low heterogeneity in lupus. The correlation of serum IL-1ra levels with serum IL-6, IL-1 beta, or TNF-alpha concentrations, and the borderline correlation of the former with CRP levels, demonstrate that IL-1ra is an acute phase reactant in RA as well as in SLE patients.     

Serum amyloid A in the assessment of early inflammatory arthritis

OBJECTIVE: Acute phase serum amyloid A (A-SAA) has been reported to be more sensitive than C-reactive protein (CRP) as a marker of disease activity. It may function in immune regulation and is linked to the development of secondary amyloidosis. We investigated the profile of A-SAA in early inflammatory arthritis and compared A-SAA with CRP and erythrocyte sedimentation rate (ESR) in relation to diagnosis and disease activity. METHODS: Using a sensitive and specific ELISA, A-SAA was measured in the serum of 140 patients with early arthritis (disease duration 2 weeks to 24 mo, mean 6 mo). CRP was determined using a standard ELISA; ESR and clinical disease activity variables were also recorded. RESULTS: Sixty-four patients had rheumatoid arthritis (RA), 19 psoriatic arthritis (PsA), 28 undifferentiated arthritis (UA), and 29 other forms of arthritis. A-SAA levels correlated with both CRP (r = 0.73, p = 0.0001) and ESR (r = 0.6, p = 0.0001). The magnitude of the A-SAA response was greater than either the CRP or ESR, and very high A-SAA levels were observed in disease as early as 2 weeks. Highest A-SAA concentrations occurred in RA (median 70.3 mg/l, maximum 1542) compared with the other groups (medians, PsA: 33 mg/l; UA: 12.3 mg/l; other arthritis: 11.2 mg/l), with values > 520 mg/l observed exclusively in RA. A-SAA, unlike CRP or ESR, could distinguish patients with a final diagnosis of RA from those who had persistent UA. In RA, A-SAA provided the strongest correlations with clinical measurements of disease activity. Clinical improvement was also best represented by A-SAA, while disease deterioration was associated with a significant increase in A-SAA values, but not CRP or ESR. CONCLUSION: Compared with ESR or CRP, A-SAA correlates best with markers of disease activity, and in patients with recent onset arthritis, very high levels of SAA occur exclusively in RA. As A-SAA is sensitive to change and accurately reflects alterations in disease status, it is the best marker available for the assessment of inflammatory joint disease.     

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.     

Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis

OBJECTIVE: An elevated acute-phase response is associated with increased radiologic damage in rheumatoid arthritis (RA), but development of damage in previously normal joints ("new joint involvement") has not previously been investigated. This study was undertaken to investigate the hypothesis that when there is suppression of disease activity as judged by the C-reactive protein level, new joint involvement is reduced to a greater extent than is progression in already damaged joints ("damaged joint progression"). METHODS: Three hundred fifty-nine patients with active RA were studied as part of a 5-year randomized, prospective, open-label study of disease-modifying antirheumatic drug therapy. Time-averaged CRP was calculated from samples obtained every 6 months, and patients were divided into groups with CRP values of <6, 6-<12, 12-<25, and > or =25 mg/liter. Radiographs of the hands and feet were scored by the Larsen method; a damaged joint was defined as one with a score of > or =2. RESULTS: The rank correlation between time-integrated CRP and increase in Larsen score was 0.50; the correlation increased to 0.59 for patients entering the study with disease duration of < or =2 years. The percentage of new joint involvement over 5 years varied markedly with time-integrated CRP, from 7.3% in the CRP <6 mg/liter group to 39.1% in the CRP > or =25 mg/liter group (5.4-fold increase). The percentage of damaged joint progression increased from 26.1% in the CRP <6 mg/liter group to 41.6% in the CRP > or =25 mg/liter group (1.6-fold increase). CONCLUSION: The results of this study provide further confirmation that high CRP levels over time are associated with greater radiologic progression. Although radiologic progression still occurred in both previously normal and damaged joints despite the presence of normal CRP levels, this consisted of proportionately less new joint involvement compared with damaged joint progression. These findings support the idea that disease-suppressive therapy should be instituted at an early stage in patients with RA, before erosive damage has occurred.     

T cell proliferative response to type II collagen in the inflammatory process and joint damage in patients with rheumatoid arthritis

OBJECTIVE: To investigate the role of T cell responses to type II collagen (CII) in disease progression in patients with rheumatoid arthritis (RA). METHODS: T cell proliferative responses to bovine CII by peripheral blood mononuclear cells (PBMC) from patients with early RA (duration < 5 yrs) were assayed by mixed lymphocyte culture. Clinical and laboratory variables including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were examined at the time of sampling. Radiographic damage on hand radiographs was evaluated by the method of Steinbrocker and Sharp. RESULTS: In a cross sectional study, patients (n = 22) with positive T cell responses (stimulation index 2) had higher levels of CRP and ESR than those (n = 21) not showing T cell responses. The number of damaged joints (by Steinbrocker's method) and damaged joint scores (by Sharp's method) were significantly higher in patients with positive T cell responses than in those without. The joint space narrowing scores correlated well with T cell responsiveness to CII. Patients (n = 15) with both positive T cell responses and RA-susceptible allotypes HLA-DR1 or DR4 had higher damaged joint scores than the remainder of the patients (n = 24). CONCLUSION: T cell proliferative responses to CII are associated with inflammatory activity and radiographic severity in RA. RA-susceptible allotypes positively relate to the radiographic progression associated with T cell responses to CII. Our data suggest that CII-reactive T cells may play a role in the pathogenic process of joint damage, especially in genetically susceptible patients.     

SDF-1 and CXCR4 in synovium are associated with disease activity and bone and joint destruction in patients with rheumatoid arthritis treated with golimumab

Objectives: The aim of this study was to determine whether the levels of stromal cell-derived factor (SDF)-1 and its receptor C-X-C chemokine receptor 4 (CXCR4) in synovium were correlated with clinical outcome and bone and joint destruction in rheumatoid arthritis (RA) patients being treated with golimumab.

Methods: Synovial tissues were obtained from 15 golimumab-treated patients and were assessed for SDF-1 and CXCR4 using a new immunohistological scoring system (IH score). The IH score was used to assess correlations between synovial SDF-1 or CXCR4 and the disease activity score (DAS28 CRP), Rooney score, tumor necrosis factor alpha, interleukin-6 (IL-6), CD4, CD20, CD68 and the Assessment of RA by Scoring of Large-Joint Destruction and Healing in Radiographic Imaging (ARASHI) score. Receiver-operating characteristic (ROC) curves were used to predict ARASHI scores from the CXCR4 IH scores.

Results: SDF-1 strongly correlated with the DAS28 CRP and serum IL-6. CXCR4 correlated with synovial CD4 and the ARASHI score. ROC analysis of CXCR4 and ARASHI scores?>10 indicated a cutoff of 12 points on the IH score for predicting joint destruction during treatment.

Conclusions: Synovial SDF-1 correlated with disease activity, and its receptor CXCR4 was related to joint destruction in RA patients treated with golimumab.     

Age adjustment corrects for apparent differences in erythrocyte sedimentation rate and C-reactive protein values at the onset of seropositive rheumatoid arthritis in younger and older patients

OBJECTIVE: To evaluate the effect of age adjustment on baseline erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with late-onset rheumatoid arthritis (LORA, age > or = 55 yrs) and younger-onset RA (YORA, age < 55 yrs) in a cohort with early, rheumatoid factor (RF) positive RA that has not received disease modifying antirheumatic drugs (DMARD). METHODS: In an ongoing prospective cohort study of 263 patients with seropositive RA who were enrolled within 14 months of symptom onset, baseline assessments included ESR, CRP, tender and swollen joint counts, and functional status. Westergren ESR determinations were performed in the rheumatologist's office or in a local laboratory using appropriate methods. CRP were performed at the Specialty Laboratories in Santa Monica, CA, using Behring nephelometry. Percentages of patients with greater than the upper limit of normal (ULN) laboratory values using both age-unadjusted and age-adjusted ESR and CRP values were determined. The late-onset and younger-onset RA patients were compared using Wilcoxon rank-sum and chi-square tests. RESULTS: At study entry, both the YORA and LORA patients had comparable symptom duration, disease activity scores, tender and swollen joint counts, and Health Assessment Questionnaire values. RF, CRP, and ESR were significantly higher (p < 0.05) in LORA patients. Although the percentages of patients with age-unadjusted ESR and CRP above ULN were higher in LORA patients, the percentages exceeding the age-adjusted ULN did not differ significantly between the YORA and LORA groups. CONCLUSION: In patients with late-onset and younger-onset RA with similar disease duration and severity, the apparent discrepancy in elevation of both the baseline ESR and CRP disappears after age-adjustment.     

The natural history and prognosis of rheumatoid arthritis: association of radiographic outcome with process variables, joint motion and immune proteins.

OBJECTIVE: The purposes of the present study were: 1) to investigate how the long-term course of outcome and inflammatory variables could be described in individual patients and suitably summarized in groups of patients; 2) to investigate the associations between outcome and inflammatory variables on the basis of the defined summary measures; and 3) to investigate new prognostic aspects of RA by means of frozen sera and DNA specimens. PATIENTS AND METHODS: During the period 1966-78, 685 Danish Caucasian patients with RA, classified according to the 1958 American Rheumatism Association (ARA) criteria, were admitted to the Department of Rheumatology of Aarhus University Hospital. For scientific purposes all patients went through the same examination programme, including biochemical variables, clinical evaluation of 68 diarthrodial joints, and radiographic evaluation of 46 diarthrodial joints. Since 1987, data from these patients have been organized in a database. The data are arranged according to onset of disease. This thesis is based on about 600,000 data-points from 257 patients. RESULTS: The thesis is based on six studies. The first study shows that early symptomatic improvement of RA during gold treatment was stable over several years, but when evaluated radiographically, the condition continued to deteriorate. In the second study, six main types of radiographic progression were identified: (a) a rare type with no radiographic progression at all (<1%); (b) a type with a slow or moderate onset, but an increasing progression rate (exponential growth type) (9%); (c) a linear type (30%); (d) a type with a moderate to fast onset, and a stable progression rate (the square root type) (11%); (e) a type with a fast onset, but a later decreasing progression rate (the first order kinetics type) (30%) and (f) a type characterized by slow onset, then acceleration and later deceleration (the sigmoid type) (20%). The fact that there was a systematic progression was used to define a system of radiographic events, which could be used as outcome measures in prediction models of the long-term course of RA. The third study shows that low serum levels of the complement-activating serum lectin, mannan (mannose) binding protein (lectin) (MBP = MBL), are associated with a higher erythrocyte sedimentation rate (ESR) (p=0.006), joint swelling score (JS score) (p=0.019), limitation of joint motion score (LM score) (p=0.027), and annual increase in radiographic destruction score (R score) (p=0.053). The fourth study demonstrated a highly significant association between summary measures of inflammatory variables and radiographic outcome, as defined in the second study, indicating that the degree of inflammation is important for the development of destructive joint damage in RA. The fifth study showed that MBL-insufficient patients (two defective structural MBL alleles, or one defective allele combined with a low-expression variant of the normal allele) had a relative risk of a severe radiographic event of 3.1 compared with the MBL competent group (p<0.0001). The sixth study showed that the relative risk (RR) of early interleukin (IL)-1alpha auto-antibodies (aAb) positive patients developing serious radiographic joint destruction was significantly lower than for IL-1alpha aAb-negative patients, RR=0.29 (p=0.04). In rheumatoid factor (RF) positive patients RR was only 0.18 (p=0.02). Patients who seroconverted >2 years after the onset of RA showed the most aggressive development of joint erosion, with RR of serious radiographic joint destruction of 2.56 (p=0.048). Other factors investigated in subgroups of the patients were HLA-DR4, chemokine receptor 5 (CCR 5) genotypes. IL-6 aAb, vascular endothelial growth factor (VEGF) aAb, and interferon (IFN)-gamma aAb. About 80% of the patients were HLA-DR4 positive, indicating the importance of HLA-DR4 as a predisposing factor for RA. There was no association between IL-6 aAb and radiographic outcome, or CCR5 genotypes and radiographic outcome. VEGF aAb and IFN-gamma aAb were quantitatively unimportant. CONCLUSION: In spite of a general improvement in single measures of inflammatory variables, and a general deterioration in radiographic outcome of RA, there is a highly significant association between summary measures of inflammatory variables and radiographic outcome. The progression of radiographic damage in RA follows mathematical patterns. A new method of evaluating the long-term radiographic outcome by means of Kaplan-Meier plots is demonstrated. It is shown that MBL and IL-1alpha aAb are predictors of the prognosis of RA and may play important roles in the pathogenesis of RA.     

Correlation of IL-6 with the classical humoral disease activity parameters ESR and CRP and with serum cortisol, reflecting the activity of the HPA axis in active rheumatoid arthritis

Zusammenfassung Die rheumatoide Arthritis (RA) ist eine systemische entzündliche Erkrankung mit erhöhten Spiegeln proinflammatorischer Zytokine im peripheren Blut, z. B. Interleukin-6 (IL-6), Interleukin-1 (IL-1) und Tumornekrosisfaktor ! (TNF!), die immunologische Aktivität der Erkrankung reflektieren. Eine veränderte zirkadiane Rhythmik des Kortisols mit insgesamt erhöhter Kortisolfreisetzung in Abhängigkeit von der entzündlichen Aktivität der RA ist bekannt. Die vorliegende Untersuchung überprüft die Korrelationen von IL-6 als den bedeutendsten systemischen Mediator der Akutphasenreaktion bei RA und klassischen Parametern der humoralen Entzündungsaktivität (Blutkörperchensenkungsgeschwindigkeit = BSG, C-reaktives Protein = CRP) sowie den Kortisolspiegeln im Serum. Wir untersuchten insgesamt 64 RA-Patienten, die bis dahin noch keine Glukokortikoidtherapie erhalten hatten, mittels Blutentnahmen morgens in der Zeit zwischen 8.30 und 9.30 Uhr. IL-6 wurde mittels ELISA bestimmt, die BSG mit der Methode nach Westergren und CRP nephelometrisch. Die Kortisolspiegel wurden bei 34 Patienten mit der Methode der Fluoreszenzpolarisation im Immunassay (FPIA) ermittelt. Wir fanden signifikante Korrelationen von IL-6 mit CRP (p < 0.001), Spearman Rank Test, r_s = 0.75), IL-6 mit der BSG (p < 0.001, r_s = 0.62) und IL-6 mit Serum-Kortisol (p = 0.019, r_s = 0.401). BSG und CRP korrelierten untereinander (p < 0.001, r_s = 0.8) und Kortisol korrelierte ebenfalls signifikant mit der BSG (p = 0.002, r_s = 0.52) und CRP (p < 0.001, r_s = 0.57). So korreliert IL-6 als wichtiger systemischer Mediator der Entzündungsreaktion bei RA eng mit CRP, dessen Produktion es induziert als auch mit der BSG. Alle drei Entzündungsparameter korrelieren darüber hinaus signifikant mit den morgendlichen Spiegeln von Serumkortisol. Die vorliegende Untersuchung belegt die enge Interaktion zwischen entzündlicher und immunologischer Aktivität der RA und der Aktivität der Achse Hypothalamus-Hypophyse-Nebennierenrinde. Summary Rheumatoid arthritis (RA) is a systemic inflammatory disease with elevated levels of proinflammatory cytokines in peripheral blood, especially IL-6, but also IL-1! and TNF!, for example, in different concentrations, depending on disease activity. A disturbed circadian rhytm of cortisol secretion and an overall elevated cortisol release in active RA, depending on disease activity, is known. The presented study examined correlations of IL-6 as the most important systemic mediator of the acute phase response in active RA with classical humoral disease activity parameters, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and with serum cortisol. We investigated 64 active RA patients, previously untreated with glucocorticoids. IL-6 was measured by ELISA from Pharmingen (San Diego), ESR by the method of Westergren and CRP by nephelometry (Behring Marburg, Germany). Cortisol was measured in 34 of these patients, using a fluorescence-polarization immunoassay (FPIA) from Abbott. We found correlations of IL-6 with CRP (p < 0.001, Spearman Rank Test, r_s = 0.75), with ESR (p < 0.001, r_s = 0.62) and with serum cortisol (p = 0.019, r_s = 0.401) ESR and CRP correlate (p < 0.001, r_s = 0.8) and cortisol also correlates with ESR (p = 0.002, r_s = 0.52) and CRP (p < 0.001, r_s = 0.57). IL-6 as an important systemic mediator of inflammation in RA correlates closely with CRP, as it induces its production, and with ESR. These three parameters correlate well with serum cortisol, which is increased in active RA, depending on disease activity. Thus, IL-6 is an important disease activity parameter in RA that is closely related to both the classical humoral disease activity and the HPA axis.     

滑膜巨噬细胞与类风湿关节炎病情活动及关节破坏的相关性

目的　了解类风湿关节炎（ＲＡ） 滑膜巨噬细胞与病情活动性及关节破坏的相关性以探讨其检测的临床意义。方法　采用ＣＤ６８ 免疫组化ＬＳＡＢ染色法检测了ＲＡ、非ＲＡ及正常滑膜巨噬细胞,并分析ＲＡ 滑膜衬里下层浸润的巨噬细胞数与ＲＡ 病情活动指标及Ｘ 线关节破坏指标之间的关系。结果　ＲＡ 滑膜衬里下层浸润的巨噬细胞数较非ＲＡ 滑膜明显增多,其不仅与关节疼痛数、关节压痛数、ＥＳＲ、ＣＲＰ等ＲＡ 病情活动指标呈明显的正相关,而且还与Ｘ 线关节破坏的侵蚀积分和狭窄积分呈明显的正相关（Ｐ＜ ０－０５ 或Ｐ＜０－０１）。结论　滑膜巨噬细胞的检测有助于ＲＡ 的病情判断（包括病情活动性及关节破坏） 及预后分析。     

The effect of individualized diet challenges consisting of allergenic foods on TNF-alpha and IL-1beta levels in patients with rheumatoid arthritis

OBJECTIVE: To investigate the effect of individualized diet challenges consisting of allergenic foods, defined by the skin prick test (SPT), on tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) levels in patients with rheumatoid arthritis (RA). METHODS: Twenty patients with a positive SPT response for food extracts and 20 with a negative SPT response were enrolled. None of the patients had active disease. All patients were fasted for the most common allergenic foods for 12 days and then allocated to two groups according to SPT results. Food challenges were performed with allergenic foods in the prick-positive group (PPG) and with corn and rice in the prick-negative group (PNG) for a period of 12 days. Then, allergenic foods were excluded from the PPG patients' diet and corn and rice were removed from the PNG patients' diet. Clinical examinations were performed after fasting (baseline), at the end of the challenge phase and at the end of the re-elimination phase. Stiffness, pain, tender and swollen joint counts, health assessment questionnaire (HAQ), Ritchie's articular index, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum TNF-alpha and IL-1beta levels were measured. RESULTS: TNF-alpha (P < 0.01), IL-1beta (P < 0.05), ESR (P < 0.05) and CRP (P = 0.001) levels and all of the clinical variables, except HAQ, were increased with food challenges in the PPG. These increases were also recorded after the re-elimination phase. In the PNG, no significant change was seen in any of the variables, except pain (P < 0.05). During the study, important differences were observed for most of the variables between the two groups. Thirteen (72%) patients in the PPG and three (18%) in the PNG experienced disease exacerbation with challenges. This aggravation continued after elimination. CONCLUSIONS: Our results suggest that individualized dietary revisions may regulate TNF-alpha and IL-1beta levels in selected patients with RA.     

Serum interleukin-23 level in rheumatoid arthritis patients: Relation to disease activity and severity

Aim of the work

The aim of this study was to evaluate interleukin-23 (IL-23) level in the sera of rheumatoid arthritis (RA) patients and to determine its relation with disease activity and severity.

Short-term outcome after anti-tumor necrosis factor-alpha therapy in rheumatoid arthritis: do we need to revise our assessment criteria?

OBJECTIVE: To evaluate the Disease Activity Score (DAS) using various aggregated dimensions to quantify treatment outcome in patients with rheumatoid arthritis (RA), in order to determine the best instrument to be used as an endpoint that indicates good response in terms of EULAR response criteria and DAS28 remission criteria, and which satisfies the demands of clinical rheumatology. METHODS: Using raw data for each patient subjected to anti-tumor necrosis factor-a therapy (81 patients), before and 6 months after treatment, DAS28 was calculated 4 times using the standard equation, as follows: (1) DAS 1 (the standard DAS28): tender joint count (TJC), swollen joint count (SJC), patient global assessment (PGA), erythrocyte sedimentation rate (ESR); (2) DAS 2: TJC, SJC, PGA, C-reactive protein (CRP); (3) DAS 3: TJC, SJC, physician global assessment (PhGA), ESR; and (4) DAS 4: TJC, SJC, PhGA, CRP. Disease activity was identified if DAS score exceeded 5.1. A clinically significant response was recorded if there had been improvement of > 1.2 of the DAS score. RESULTS: DAS 2, DAS3, and DAS4 were superior to the current DAS score used for assessment of RA activity (effect size differences were -0.35, -0.13, and -0.48, respectively). Assessment of disease activity using TJC, SJC, PhGA, and CRP was the best tool to assess response to therapy. ESR was marginally superior to CRP in its sensitivity to monitor disease activity changes (effect sizes 1.08 and 1.03, respectively). CONCLUSION: These results suggest that self-report indices on their own, such as PGA and pain score, are inadequate indicators of disease activity. The DAS might profitably be amended by one or 2 continuous measures for better quantification of the degree of improvement of patients on a given therapeutic modality. Using PhGA and CRP instead of PGA and ESR, respectively, in the DAS equation discriminated better between different patients' responses than the traditional DAS score.