Cardiovascular risk management in gout patients: do patients benefit from screening in secondary care?

OBJECTIVES: To estimate the 10-year cardiovascular disease (CVD) risk in gout patients in secondary care and to evaluate the effect of CVD risk screening on the 10-year CVD risk after 1 year. METHODS: A prospective cohort study was performed in patients with gout from Reade Amsterdam. Data on gout and CVD history, traditional risk factors, medication, and lifestyle were collected at baseline and 1 year. The 10-year CVD risk was calculated with the use of the NL-SCORE. A paired sample t-test and McNemar test was performed to test for differences between baseline and the 1-year visit. RESULTS: A very high prevalence of traditional CV risk factors was seen in our secondary care gout patients. Nineteen percent without previous CVD were categorised in the high-risk group according the NL-SCORE. The prevalence of CVD increased from 16% to 21% after 1-year follow-up. A decrease was seen in total- and LDL-cholesterol after 1 year. No decrease in mean BMI, waist-hip ratio, blood pressure or NL-SCORE was observed. CONCLUSIONS: The current need for CVD risk screening of gout patients in secondary care was illustrated by the high prevalence of traditional risk factors in this cohort. Recommendations to patients and the general practitioner (GP) alone did not result in overall improvement of traditional CVD risk factors nor the 10-year CVD risk. Our results indicate that a more prominent role of the rheumatologist is necessary to optimise the process of initiation and management of CVD risk in gout patients.

MRP8/14 serum levels as a strong predictor of response to biological treatments in patients with rheumatoid arthritis.

BACKGROUND: One-third of rheumatoid arthritis (RA) patients treated with biological therapy show lack of response. The use of predictive biomarkers to identify responders to treatment may provide guidance in optimising treatment strategies and reduce unnecessary side effects and costs. OBJECTIVE: To test the ability of myeloid-related proteins (MRP)8/14 protein complexes, an endogenous TLR-4 receptor agonist, to predict and monitor response to biologics in RA patients. METHODS: 170 RA patients treated with adalimumab (n=86), infliximab (n=60) or rituximab (n=24) were categorised into clinical responders (n=123) and non-responders (n=47). MRP8/14 serum complexes were measured at baseline, and 4 and 16 weeks after initiation of treatment and related to response outcome. RESULTS: Before initiation of treatment, responders showed significantly higher MRP8/14 protein complex levels compared with non-responders in each prospective cohort (p=0.010, p=0.001 and p<0.001, respectively). Logistic regression analysis showed that having high MRP8/14 baseline levels increased the odds of being a responder by 3.3 up to 55. In responders to adalimumab or infliximab treatment, MRP8/14 levels decreased after 4 weeks of treatment by 46% and 60% and after 16 weeks by 61% and 68%, respectively. In contrast, MRP8/14 levels were stable in non-responders. In patients treated with rituximab, MRP8/14 levels decreased by 59% after 16 weeks in responders and increased by 89% after 16 weeks in non-responders. CONCLUSION: Serum concentrations of MRP8/14 protein complex are a promising biomarker to predict response to biological therapy in active RA patients at baseline and could be used to monitor response to treatment across different mechanisms of action.

Local synovial engagement of angiogenic TIE-2 is associated with the development of persistent erosive rheumatoid arthritis in patients with early arthritis.

OBJECTIVE: To examine the role of vascular endothelial growth factor (VEGF) and angiopoietin signaling in the diagnosis and disease outcome of patients with early arthritis. METHODS: Fifty patients with early arthritis (disease duration <1 year) who had not been treated with disease-modifying antirheumatic drugs (DMARDs) were monitored prospectively and were classified at baseline and after 2 years as having undifferentiated arthritis (UA), rheumatoid arthritis (RA), or spondyloarthritis (SpA). All patients underwent arthroscopic synovial biopsy at baseline. Synovial expression of VEGF, VEGF receptor, angiopoietin 1 (Ang-1), Ang-2, TIE-2, and activated p-TIE-2 was evaluated by immunohistochemistry. Serum levels of VEGF, Ang-1, and Ang-2 were measured by enzyme-linked immunosorbent assay. Secreted products of macrophages stimulated with Ang-1 and Ang-2 were measured using a multiplex system. RESULTS: Expression of Ang-1 was comparable between the patients with RA at baseline and patients with UA who fulfilled the criteria for RA over time (UA/RA), and it was significantly higher in patients with RA (P < 0.05) or UA/RA (P < 0.005) than in patients with SpA. TIE-2 and p-TIE-2 were more highly expressed in patients with RA (P < 0.005) or UA/RA (P < 0.05) than in patients with SpA. Ang-1 significantly enhanced the tumor necrosis factor-dependent macrophage production of cytokines and chemokines that are known to be elevated in the synovial fluid of patients with early RA. In RA, relative TIE-2 activation predicted the development of erosive disease (R(2) = 0.35, P < 0.05). CONCLUSION: Local engagement of synovial TIE-2 is observed during the earliest phases of RA, suggesting that TIE-2 signaling may contribute to disease development and progression or may indicate an attempt to protect against these processes. Early therapeutic targeting of TIE-2 signaling may be useful in improving outcome in arthritis.

Anti-TNF therapy reduces serum levels of chemerin in rheumatoid arthritis: a new mechanism by which anti-TNF might reduce inflammation.

BACKGROUND: Chemerin is a specific chemoattractant for macrophages and dendritic cells (DC). In addition, it can rapidly stimulate macrophage adhesion to extracellular matrix proteins and adhesion molecules and is able to activate fibroblast-like synoviocytes (FLS), suggesting a role in the pathogenesis of rheumatoid arthritis (RA). Chemerin is also an adipocytokine that has been related to the inflammatory state of endothelial cells and as such could be involved in the changes in endothelial cells in RA and perhaps increased cardiovascular morbidity. We investigated whether anti-Tumor Necrosis Factor (TNF) treatment affects chemerin levels. MATERIALS AND METHODS: 49 patients with active RA (disease activity score evaluated in 28 joints (DAS28) ≥3.2) were started on adalimumab therapy. Blood was drawn from patients while fasting at baseline and 16 weeks after initiation of treatment. Chemerin serum levels were measured by ELISA and related to disease activity, mediators of inflammation and known risk factors for cardiovascular disease. RESULTS: Adalimumab therapy reduced chemerin serum levels, which was correlated with the reduction in DAS28 (r = 0.37, p = 0.009). In addition, the decrease in chemerin serum levels after anti-TNF treatment was associated with the decrease in serum levels of IL-6 (r = 0.39, p = 0.033) and macrophage migration inhibitory factor (MIF) (r = 0.31, p = 0.049). Baseline chemerin serum levels were not related to traditional risk factors for atherosclerosis, except perhaps for smoking (p = 0.07). CONCLUSIONS: This exploratory study shows that adalimumab therapy lowers chemerin levels, which is associated with the reduction in disease activity parameters, and inflammatory mediators IL-6 and MIF. This suggests a possible involvement of chemerin in the migration/retention of macrophages in the synovium. TRIAL REGISTRATION NEDERLANDS TRIAL REGISTER: NTR 857.

The features of the synovium in early rheumatoid arthritis according to the 2010 ACR/EULAR classification criteria.

OBJECTIVES: It has been shown in early arthritis cohorts that the 2010 ACR/EULAR criteria for rheumatoid arthritis (RA) enable an earlier diagnosis, perhaps at the cost of a somewhat more heterogeneous patient population. We describe the features of synovial inflammation in RA patients classified according to these new criteria. METHODS: At baseline, synovial tissue biopsy samples were obtained from disease-modifying antirheumatic drug (DMARD)-naïve early RA patients (clinical signs and symptoms <1 year). Synovial tissue was analyzed for cell infiltration, vascularity, and expression of adhesion molecules. Stained sections were evaluated by digital image analysis. Patients were classified according to the two different sets of classification criteria, autoantibody status, and outcome. FINDINGS: Synovial tissue of 69 RA patients according to 2010 ACR/EULAR criteria was analyzed: 56 patients who fulfilled the criteria for RA at baseline and 13 who were initially diagnosed as undifferentiated arthritis but fulfilled criteria for RA upon follow up. The synovium at baseline was infiltrated by plasma cells, macrophages, and T cells as well as other cells, and findings were comparable to those when patients were selected based on the 1987 ACR criteria for RA. There was no clear cut difference in the characteristics of the synovium between RA patients initially diagnosed as undifferentiated arthritis and those who already fulfilled classification criteria at baseline. CONCLUSION: The features of synovial inflammation are similar when the 2010 ACR/EULAR classification criteria are used compared to the 1987 ACR criteria.

Characteristics of synovial inflammation in early arthritis analysed by pixel-by-pixel time-intensity curve shape analysis.

OBJECTIVE: Dynamic contrast-enhanced (DCE-MRI) time-intensity curve (TIC) shape analysis has previously been used in oncology, where fast initial enhancement and early washout are associated with malignancy. As RA synovium has some tumour-like features, we investigated DCE-MRI TIC shape expression in early arthritis in relationship to diagnosis. METHODS: Twenty-eight DMARD-naïve, early arthritis patients (<1 year) with inflammation of at least one knee joint were included. At baseline DCE-MRI of the inflamed knee joint was performed, and the TIC shape type expression, maximal enhancement, maximum slope of increase and total volume of enhancing pixels were calculated. In addition, disease activity parameters were determined. At 2 years of follow-up, patients were classified as RA or non-RA according to established classification criteria. RESULTS: Type 4 TIC shape, characterized by fast initial enhancement followed by a quick washout phase, was significantly higher in patients fulfilling classification criteria for RA after 2 years of follow-up compared with non-RA patients (15.6 and 7.9%, respectively, P = 0.02). All other DCE-MRI parameters showed no differences between the groups, highlighting the specificity of this observation. CONCLUSION: A high expression of aggressive DCE-MRI TIC shape Type 4 is associated with RA. Our results are consistent with the view that increased vascularity plays a key role in the pathogenesis of RA. This study underlines the rationale for further studies investigating the prospect of DCE-MRI TIC shape analysis as a diagnostic tool in early arthritis and the relationship with development of destructive disease.

Body mass index and clinical response to infliximab in rheumatoid arthritis.

OBJECTIVE: Adipose tissue has immunomodulating effects in rheumatoid arthritis (RA), although the exact role is, at present, unclear. The purpose of this study was to determine whether body mass index (BMI) affects response to infliximab in RA patients investigated prospectively. METHODS: In 89 patients with active RA, the BMI was calculated before initiation of infliximab treatment (3 mg/kg intravenously). After 16 weeks of treatment, changes in disease activity were assessed with the Disease Activity Score in 28 joints (DAS28). RESULTS: The mean ± SD BMI was 26 ± 5 kg/m(2) (range 17-42). The BMI correlated positively with the DAS28 at baseline (r = 0.34, P = 0.001). Since selection of study patients according to DAS28 values could influence the clinical response to tumor necrosis factor (TNF) blockade due to regression to the mean because the clinical response is itself based on the change in the DAS28 values, analysis of covariance was used to correct for the baseline DAS28. A highly significant, negative association between the BMI and the absolute decrease in the DAS28 after 16 weeks (P = 0.001) was found also when adjusted for anti-citrullinated protein antibodies. CONCLUSION: Although the infliximab dosage is based on body weight, RA patients with a high BMI responded less well to infliximab, a finding that held true when adjusted for the baseline DAS28 or anti-citrullinated protein antibody status. These results support the notion that adipose tissue may be involved in the pathophysiology of RA and could have implications for other immune-mediated inflammatory conditions treated with TNF antagonists.

Presence of lymphocyte aggregates in the synovium of patients with early arthritis in relationship to diagnosis and outcome: is it a constant feature over time?

OBJECTIVES: To evaluate the presence of lymphocyte aggregates in synovial tissue of patients with early arthritis in relationship to clinical outcome and to determine whether this is a stable feature over time. METHODS: Arthroscopic synovial biopsy samples were collected in a prospective cohort of disease-modifying antirheumatic drug-naïve patients with early arthritis (<1 year's disease duration) at baseline (n=93) and, if rheumatoid arthritis was suspected, after 6 months of follow-up (n=17). After 2 years of follow-up, definitive diagnosis and clinical outcome were assessed. Size of synovial lymphocyte aggregates was graded (score 1-3). Lymphoid neogenesis (LN) was defined by the presence of grade ≥2 aggregates and subclassified based on the presence of follicular dendritic cells (FDCs). RESULTS: LN was present in 36% of all patients and FDCs in 15% of patients with LN. Presence of lymphocyte aggregates differed over time. LN was associated with the degree of synovial inflammation. There was no relationship between the presence of lymphocyte aggregates at baseline and definitive diagnosis or clinical outcome after follow-up. CONCLUSIONS: Presence of lymphocyte aggregates is a dynamic phenomenon related to the degree of synovitis and can be detected in different forms of early arthritis. This feature does not appear to be related to clinical outcome.

The gene expression profile in the synovium as a predictor of the clinical response to infliximab treatment in rheumatoid arthritis.

BACKGROUND: Although the use of TNF inhibitors has fundamentally changed the way rheumatoid arthritis (RA) is treated, not all patients respond well. It is desirable to facilitate the identification of responding and non-responding patients prior to treatment, not only to avoid unnecessary treatment but also for financial reasons. In this work we have investigated the transcriptional profile of synovial tissue sampled from RA patients before anti-TNF treatment with the aim to identify biomarkers predictive of response. METHODOLOGY/PRINCIPAL FINDINGS: Synovial tissue samples were obtained by arthroscopy from 62 RA patients before the initiation of infliximab treatment. RNA was extracted and gene expression profiling was performed using an in-house spotted long oligonucleotide array covering 17972 unique genes. Tissue sections were also analyzed by immunohistochemistry to evaluate cell infiltrates. Response to infliximab treatment was assessed according to the EULAR response criteria. The presence of lymphocyte aggregates dominated the expression profiles and a significant overrepresentation of lymphocyte aggregates in good responding patients confounded the analyses. A statistical model was set up to control for the effect of aggregates, but no differences could be identified between responders and non-responders. Subsequently, the patients were split into lymphocyte aggregate positive- and negative patients. No statistically significant differences could be identified except for 38 transcripts associated with differences between good- and non-responders in aggregate positive patients. A profile was identified in these genes that indicated a higher level of metabolism in good responding patients, which indirectly can be connected to increased inflammation. CONCLUSIONS/SIGNIFICANCE: It is pivotal to account for the presence of lymphoid aggregates when studying gene expression patterns in rheumatoid synovial tissue. In spite of our original hypothesis, the data do not support the notion that microarray analysis of whole synovial biopsy specimens can be used in the context of personalized medicine to identify non-responders to anti-TNF therapy before the initiation of treatment.

Synovial tissue heterogeneity in rheumatoid arthritis in relation to disease activity and biomarkers in peripheral blood.

OBJECTIVE: To investigate the clinical relevance of synovial tissue subtypes in rheumatoid arthritis (RA) and to search for peripheral blood (PB) markers that may serve as biomarkers for tissue subtypes. METHODS: Gene expression analysis using complementary DNA microarrays was applied on paired synovial tissue biopsy and PB samples obtained from 17 RA patients. Molecular tissue subtypes were correlated with histologic parameters (CD3, CD22, CD38, CD68, CD163, tumor necrosis factor alpha, intercellular adhesion molecule 1, vascular cell adhesion molecule, and E-selectin), disease characteristics, and PB markers. PANTHER classification was used for pathway analysis. RESULTS: Genomic subtyping of high- and low-inflammation rheumatoid synovial tissues based on gene expression profiles exactly matched immunohistochemical classification. The patients with the high-inflammation tissue type had higher Disease Activity Scores in 28 joints, higher C-reactive protein levels, higher erythrocyte sedimentation rates, increased numbers of platelets, and shorter disease durations. Comparative analysis of PB gene expression profiles yielded no statistically significant differences between the 2 tissue groups at the single-gene expression level. PANTHER pathway analysis revealed a significant association of increased protein biosynthesis with high-inflammation tissue. CONCLUSION: High-inflammation tissue is associated with more severe disease and shorter disease duration. While pathway-level analysis revealed that coordinate differential expression of genes involved in protein synthesis in PB is associated with high-inflammation tissue types, differential tissue pathology was not reflected in the PB by differential expression of single genes.

Regulation of IFN response gene activity during infliximab treatment in rheumatoid arthritis is associated with clinical response to treatment.

INTRODUCTION: Cross-regulation between TNF and type I IFN has been postulated to play an important role in autoimmune diseases. Therefore, we determined the effect of TNF blockade in rheumatoid arthritis (RA) on the type I IFN response gene activity in relation to clinical response. METHODS: Peripheral blood from 33 RA patients was collected in PAXgene tubes before and after the start of infliximab treatment. In a first group of 15 patients the baseline expression of type I IFN-regulated genes was determined using cDNA microarrays and compared to levels one month after treatment. The remaining 18 patients were studied as an independent group for validation using quantitative polymerase chain reaction (qPCR). RESULTS: Gene expression analysis revealed that anti-TNF antibody treatment induced a significant increase in type I IFN response gene activity in a subset of RA patients, whereas expression levels remained similar or were slightly decreased in others. The findings appear clinically relevant since patients with an increased IFN response gene activity after anti-TNF therapy had a poor clinical outcome. This association was confirmed and extended for an IFN response gene set consisting of OAS1, LGALS3BP, Mx2, OAS2 and SERPING1 in five EULAR good and five EULAR poor responders, by qPCR. CONCLUSIONS: Regulation of IFN response gene activity upon TNF blockade in RA is not as consistent as previously described, but varies between patients. The differential changes in IFN response gene activity appear relevant to the clinical outcome of TNF blockade in RA.

Type I interferons have no major influence on humoral autoimmunity in rheumatoid arthritis.

OBJECTIVE: Type I IFNs have recently been implicated in autoantibody-mediated diseases such as SLE. As half the RA patients display a type I IFN(high) signature, we investigated in a pilot study if type I IFN determines the autoantibody response in RA. METHODS: Serum and peripheral blood cells were obtained from 52 RA patients, with paired samples before and after infliximab treatment in 21 patients. Additional samples were collected from 8 anti-citrullinated protein antibody (ACPA)-positive individuals without arthritis and from 10 ACPA-negative healthy controls. The type I IFN signature was determined by peripheral blood cell gene expression analysis and quantitative RT-PCR. ACPA IgG and IgM, RF IgM, anti-nucleosome IgM and anti-dsDNA were measured by ELISA. RESULTS: The type I IFN signature was not related to the presence and titers of ACPA and RF during active disease. TNF blockade induced a similar rise of ANAs, and a similar decrease in RF titers in both groups. ACPA IgG and IgM levels appeared to be down-modulated only in the type I IFN(low) group. These changes were independent of the changes in type I IFN response gene activity after TNF blockade. Furthermore, the ACPA response in individuals without arthritis and inflammation was not related to an increase of type I IFN. CONCLUSIONS: In this explorative study, type I IFN signature does not appear to have a major impact on the humoral autoimmune response in RA. Replication of these data remains warranted.

The relationship between synovial lymphocyte aggregates and the clinical response to infliximab in rheumatoid arthritis: a prospective study.

OBJECTIVE: Some patients with rheumatoid arthritis (RA) exhibit lymphocyte aggregates in the synovium. This study was undertaken to address whether the presence of lymphocyte aggregates before treatment could serve as a biomarker for the clinical response to tumor necrosis factor (TNF) blockade, and to confirm whether the aggregation of synovial lymphocytes is reversible after anti-TNF treatment. METHODS: Synovial tissue biopsy samples were obtained from 97 patients with active RA before the initiation of infliximab treatment. Lymphocyte aggregates in the synovial tissue were counted and also graded for size. Logistic regression analysis was performed to identify whether the presence of lymphocyte aggregates could be a predictor of the clinical response at week 16. Furthermore, the effects of TNF blockade on lymphocyte aggregates were compared between patients with RA and patients with psoriatic arthritis (PsA). RESULTS: Fifty-seven percent of RA synovial tissue samples contained lymphocyte aggregates, and 32% of the patients had large aggregates. Aggregates were found in 67% of clinical responders compared with 38% of nonresponders. The presence of aggregates at baseline was a highly significant predictor of the clinical response to anti-TNF treatment (R(2) = 0.10, P = 0.008). Positivity for lymphocyte aggregates increased the power to predict the clinical response (R(2) = 0.29), when analyzed in a prediction model that included baseline disease activity evaluated by the Disease Activity Score in 28 joints, anti-cyclic citrullinated peptide antibody positivity, and synovial TNFalpha expression. There was a reduction in lymphocyte aggregates after anti-TNF antibody therapy in both RA and PsA. CONCLUSION: RA patients with synovial lymphocyte aggregates have, on average, a better response to infliximab treatment than those with only diffuse leukocyte infiltration. Moreover, the aggregation of synovial lymphocytes is reversible after anti-TNF antibody treatment.

Analysis of apoptosis in peripheral blood and synovial tissue very early after initiation of infliximab treatment in rheumatoid arthritis patients.

OBJECTIVE: Infliximab treatment results in a decrease in synovial cellularity as early as 48 hours after initiation of therapy in patients with rheumatoid arthritis (RA). This study was undertaken to investigate whether infliximab induces apoptosis within the first 24 hours after infusion. METHODS: The percentage of apoptotic cells was determined by flow cytometry in blood drawn from 21 patients directly before, 1 hour after, and 24 hours after infliximab infusion. Synovial tissue samples obtained before, 1 hour after (n = 5), or 24 hours after (n = 5) initiation of therapy were subjected to immunohistochemistry to detect active caspase 3 and to TUNEL assay and electron microscopy to detect apoptosis. In addition, plasma levels of nucleosomes (generated during apoptosis) and C4b/c (an indicator of complement activation) were measured. RESULTS: There were no signs of apoptosis induction in peripheral blood monocytes or lymphocytes after infliximab treatment. Circulating lymphocyte counts were increased within 1 hour after infusion (P < 0.05). There was no definite evidence of apoptosis induction in the synovium, except in 1 patient 24 hours after the infliximab infusion. Consistent with these results, there was no increase in nucleosome levels nor were there signs of complement activation. CONCLUSION: Our findings indicate that the rapid decrease in synovial cellularity observed after initiation of anti-tumor necrosis factor antibody therapy cannot be explained by apoptosis induction at the site of inflammation. It is tempting to speculate that the striking effects on synovial inflammation may be explained by other mechanisms, such as decreased migration toward the synovial compartment and reduced retention in the inflamed synovium.

Synovial lymphoid neogenesis does not define a specific clinical rheumatoid arthritis phenotype.

OBJECTIVE: To investigate the relationship between lymphoid neogenesis in the synovium of patients with rheumatoid arthritis (RA) and characteristics of inflammation and disease severity. METHODS: Arthroscopic synovial biopsy was performed in 103 patients with active RA (Disease Activity Score 28-joint assessment >or=3.2) who had not received treatment with biologic agents. Sections were stained and assessed by digital image analysis. Lymphocyte aggregates were counted and graded for size (1-3). Synovial lymphoid neogenesis was defined as the presence of grade 2 or 3 aggregates and subclassified based on the presence of follicular dendritic cells (FDCs). RESULTS: Lymphoid neogenesis was present in 31% of the RA synovial tissues, whereas an additional 25% contained only grade 1 aggregates. FDCs were present in 28% of the samples with lymphoid neogenesis, corresponding to 8% of the total RA cohort. Histologically, synovia with lymphoid neogenesis showed increased infiltration by T and B lymphocytes, plasma cells, and macrophages, and increased expression of tumor necrosis factor alpha and lymphotoxin beta compared with samples without lymphoid neogenesis. Patients with lymphoid neogenesis also had higher C-reactive protein levels, erythrocyte sedimentation rates, and leukocyte and thrombocyte counts, but exhibited no increase in the severity of clinical signs and symptoms. Of importance, there was no relationship between the presence of lymphoid neogenesis and IgM rheumatoid factor or anti-citrullinated protein antibodies. The presence of lymphocyte aggregates with FDCs did not define a specific clinical phenotype compared with lymphocyte aggregates without FDCs. CONCLUSION: These findings indicate that synovial lymphoid neogenesis is associated with more severe synovial and systemic inflammation, but this is not confined to a specific clinical subset of RA.

Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti-tumor necrosis factor therapy in rheumatoid arthritis.

OBJECTIVE: Some patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) improve rapidly from anti-tumor necrosis factor (anti-TNF) therapy. No sensitive markers are available that might predict outcome of anti-TNF therapy. We undertook this study to investigate the predictive value of hypothalamic-pituitary-adrenal (HPA) axis hormones for clinical improvement during anti-TNF therapy. METHODS: An observational study in 23 RA patients was followed by a validation study in 38 RA patients. The patients receiving anti-TNF antibodies had no glucocorticoid treatment, and we measured baseline serum levels of adrenocorticotropic hormone (ACTH) and cortisol. Improvement during anti-TNF antibody treatment was judged by the Disease Activity Score in 28 joints (DAS28), and serum levels of cortisol were measured at followup. RESULTS: The observational study demonstrated that improvement in the DAS28 correlated negatively with baseline serum levels of cortisol (R=-0.520, P=0.011) and the cortisol:ACTH ratio (R=-0.700, P=0.0002). In the longitudinal part of the study at followup, those patients with good improvement and initially low serum levels of cortisol demonstrated an increase of serum cortisol, in contrast to patients with little or no improvement. Findings in the observational study were supported by those in the validation study in a group of RA patients with less inflammation (correlation of improvement in the DAS28 with cortisol:ACTH ratio: R=-0.320, P=0.025). CONCLUSION: This is the first study in a human chronic inflammatory disease to demonstrate that inflammation-induced TNF interferes with HPA axis integrity, which is linked to the disease outcome. These findings position the HPA axis centrally in the vicious circle of perpetuation of chronic inflammation.

The Academic Medical Center Linear Disability Score item bank: psychometric properties of a new generic disability measure in rheumatoid arthritis.

OBJECTIVE: To determine the psychometric properties of the Academic Medical Center (AMC) Linear Disability Scale (ALDS) item bank in a population of patients with rheumatoid arthritis (RA). METHODS: 129 patients with RA completed the ALDS and Health Assessment Questionnaire Disability Index (HAQ-DI) at baseline, and after 8 and 16 weeks of anti-tumor necrosis factor-alpha treatment. Disease activity assessments at these timepoints included serum levels of C-reactive protein, Disease Activity Score 28, morning stiffness, and visual analog scales for global disease activity and fatigue. RESULTS: Reliability of the ALDS was excellent (homogeneity, Cronbach's alpha = 0.95; test-retest, intraclass correlation coefficient = 0.93). The ALDS results at baseline were strongly correlated with the HAQ-DI (r = -0.75). With regard to known group validity, both instruments discriminated between higher and lower disease activity (ALDS, p < 0.0001; HAQ-DI, p = 0.002) and between non-, moderate, and good responders (ALDS, p = 0.002; HAQ-DI, p < 0.0001), indicating that both instruments differentiate between groups. The ALDS was moderately to highly responsive to changes between baseline and after 8 weeks and 16 weeks of treatment (standardized response mean, range = 0.71-1.19). No substantial floor or ceiling effects were found. CONCLUSION: Our results show that the ALDS is a promising new instrument, with at least equivalent psychometric properties compared to the HAQ-DI. Advantages of the ALDS item bank are its linear structure and an item bank that can be adapted depending on the ability level of the patient.

Early effects of rituximab on the synovial cell infiltrate in patients with rheumatoid arthritis.

OBJECTIVE: To study the specific effects of rituximab treatment on the synovium in patients with rheumatoid arthritis (RA) early after initiation of treatment. METHODS: Seventeen RA patients underwent an arthroscopic synovial biopsy procedure directly before and 1 month after receiving 2 infusions of the chimeric anti-CD20 monoclonal antibody rituximab (1,000 mg on days 1 and 15; both without methylprednisolone premedication). Immunohistochemical analysis was performed to characterize the cell infiltrate. Stained tissue sections were analyzed by digital image analysis. Statistical analysis was performed using Wilcoxon's signed rank test. RESULTS: No significant change in the Disease Activity Score 28-joint assessment was found at 4 weeks after the first rituximab infusion. At 2 and 4 weeks after infusion, B cells in peripheral blood were almost completely depleted. Most B cells in the synovium were found in large lymphocyte aggregates. Interestingly, a significant reduction in B cell numbers at sites of inflammation was observed 4 weeks after treatment (median 26 cells/mm(2) [interquartile range 4-150] before treatment and 11 cells/mm(2) [interquartile range 0-29] after treatment; P < 0.02). B cells disappeared completely in 3 patients, whereas there was partial depletion in 11 patients. In the other 3 patients, no B cells were present in biopsy tissues obtained either pretreatment or posttreatment. No reductions in other synovial cell populations were observed at 4 weeks. CONCLUSION: Rituximab treatment leads to a rapid and significant decrease in synovial B cell numbers, but not in all patients. Whether the variable tissue response is related to the clinical response over time remains to be clarified.

Synovial macrophages as a biomarker of response to therapeutic intervention in rheumatoid arthritis: standardization and consistency across centers.

Successive studies from one academic center (Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands) have consistently suggested that synovial tissue expression of sublining macrophages may be a biomarker of clinical response to therapeutic intervention in rheumatoid arthritis (RA) clinical trials. A proof-of-concept, randomized clinical trial was completed at a second academic center (St. Vincent's University Hospital, Dublin, Ireland), and the relationship between the change in disease activity and the change in sublining macrophages in distinct treatment cohorts was determined. The preliminary findings were not conclusive, but appeared to support a role for sublining CD68+ macrophages as a biomarker of clinical response to therapeutic intervention in cohorts of patients with RA.