Perceptions of the Cause, Impact and Management of Persistent Fatigue in Patients with Rheumatoid Arthritis Following Tumour Necrosing Factor Inhibition Therapy.

INTRODUCTION: Fatigue is a major symptom of rheumatoid arthritis (RA), the most common chronic inflammatory joint disease. The present study explored patients' experiences of RA fatigue to elucidate unique elements and management strategies. METHODS: This single site study recruited tumour necrosis factor-α inhibitor (TNFi)-treated RA patients with a moderate/good response in disease activity and persistent moderate/greater fatigue on a five-point verbal rating scale. This qualitative descriptive design used semi-structured questions, individual interviews and content analysis of narrative data. RESULTS: Ten patients were interviewed (six women), with age and disease duration ranges of 44-75 and 6-36 years, respectively. Perceptions of the RA fatigue experience generated four categories (experiencing a distinct, yet seldom discussed RA symptom; seeking an explanation for fatigue; being in an incapacitating state; and trying to manage) and eight subcategories. Fatigue was newly identified as a distinct part of the entity of RA. While patients proposed many plausible root causes, the only rational explanation for the nature of this fatigue was that it was integral to their RA. Singularly, fatigue contributed considerably to RA-imposed lifestyle restrictions. Patients had learnt to accommodate and self-manage fatigue in the absence of professional input. Novel management strategies proposed included patients talking about the nature of RA fatigue with others and the need for staff to alert patients to this distinct symptom of RA. CONCLUSION: Fatigue, branded as a distinct symptom of RA, exerted an identifiable impact on patients. Fatigue is potentially amenable to modification; talking about fatigue was proposed as a novel management strategy. Copyright © 2016 John Wiley & Sons, Ltd.

Factors that influence fatigue status in patients with severe rheumatoid arthritis (RA) and good disease outcome following 6 months of TNF inhibitor therapy: a comparative analysis.

The objective of the present study is to determine the factors associated with persistent fatigue in patients with severe rheumatoid arthritis (RA) and good disease response to 6 months of tumour necrosis factor inhibitor therapy. Eligible patients with either persistent (PF) or no fatigue (NF) were compared. Using validated questionnaires and bivariate analysis, this cross-sectional survey explored if clinical characteristics, pain, self-efficacy, sleep and mood/depression differed between groups. Patients with PF (PF; NF) (n = 28; 28) reported significantly more overall pain (11.3 ± 9.4 (0-33); 6.9 ± 8.9 (0-33)), more recent and current pain intensity (41.4 ± 26.6 (0-80) 24.4 ± 26.6 (0-100) and depression (11.8 ± 7.5 (1-35); 8.2 ± 6.6 (0-26)), than the NF group. There was no significant difference between groups in self-efficacy and both groups experienced poor sleep quality (Pittsburgh Sleep Quality Index >5). Despite having good disease response, the PF group had significantly higher rheumatoid factor incidence, disease activity score-28, early morning stiffness duration and lower incidence of ever-failing disease-modifying anti-rheumatic drugs than the NF group. These findings enhance the fatigue literature in patients with RA prescribed tumour necrosis factor (TNF) inhibition therapy, identifying the potentially modifiable factors of pain and depression, previously demonstrated to be strongly associated with fatigue in non-biologic populations. In addition, this study highlights the association between persistent fatigue and an on-going state of low disease activity. This infers that more judicious disease management could minimise the symptom burden of pain and depression and consequentially fatigue.

How much is fatigue explained by standard clinical characteristics of disease activity in patients with inflammatory arthritis? A longitudinal study.

OBJECTIVE: To determine the relationship between fatigue and the American College of Rheumatology (ACR) core set outcomes in patients with inflammatory arthritis (IA). METHODS: This prospective longitudinal study evaluated fatigue in patients with active IA commencing tumor necrosis factor (TNF) inhibitor therapy. Fatigue was assessed using the multidimensional assessment of fatigue scale and the ACR core set (swollen and tender joint counts, pain, global health score, Health Assessment Questionnaire [HAQ] disability index [DI], and C-reactive protein level) was used for standard assessment of disease activity. RESULTS: Assessments at baseline, 3 months, and 6 months were completed by 125, 92, and 82 patients, respectively. Fatigue and disease activity improved significantly within the first 3 months, with fatigue improving by 29% (F[2, 118] = 17.14, P < 0.001; repeated-measures analysis of variance). Using multiple regression, the amount of fatigue explained by the core outcomes differed at each time point: 28% at baseline (P < 0.001; significant predictors were the HAQ DI, global health, and C-reactive protein level), 37% at 3 months (P < 0.001; significant predictors were pain and tender joint count), and 46% at 6 months (P < 0.001; significant predictor was global health). Regression modelling using the fatigue change score at 3 months explained 17% of fatigue change (P < 0.012; significant predictors were HAQ DI and global health). CONCLUSION: Fatigue, which improved following treatment with TNF inhibitors, was poorly and inconsistently explained through the core set outcomes. Further, fatigue was least accounted for when the disease was most active, highlighting the need for further research into alternate explanations. These findings suggest further exploration of contributing variables and mechanisms in order to develop targeted symptom management of fatigue in IA.

Pulmonary fibrosis in systemic sclerosis: association with myocardial fibrosis.

PURPOSE: To evaluate the relationship between pulmonary and myocardial fibrosis in patients with systemic sclerosis (SS). MATERIALS AND METHODS: Eighteen patients with SS prospectively underwent cardiac magnetic resonance imaging (CMR) and high-resolution computed tomography (HRCT) of the chest. Cardiac biomarkers (N-terminal pro B-type natriuretic peptide) and quality-of-life measures (SF-36 and SS health assessment questionnaires) were assessed. Two readers blinded to other test results evaluated the CMRs in consensus for functional left and right ventricular parameters and for myocardial late enhancement. HRCT images were reviewed at 5 levels and scored for total disease extent, extent of reticulation, proportion of ground-glass opacities (GGO), and coarseness of reticulation. RESULTS: Right ventricular ejection fraction correlated significantly with the percentage of late enhancement of the myocardium (R=0.63, P<0.01), extent of pulmonary fibrosis (R=0.57, P<0.01), and extent of GGO (R=0.53, P<0.05). Significant correlations were also found between the percentage of late enhancement of the myocardium and the extent of overall pulmonary fibrosis (R=0.59, P<0.05) and the extent of the ground-glass subcomponent (R=0.58, P<0.05). N-terminal pro B-type natriuretic peptide correlated significantly with the number of myocardial segments with late enhancement (R=0.64, P<0.05). Stepwise multiple linear regression revealed the extent of pulmonary GGO to be the only independent predictor of the percentage of myocardial enhancement (R2=0.61, P<0.0001). CONCLUSION: In patients with SS with pulmonary fibrosis on HRCT images, CMR may be a useful test to detect early-stage myocardial fibrosis.

Acute-phase serum amyloid A regulates tumor necrosis factor α and matrix turnover and predicts disease progression in patients with inflammatory arthritis before and after biologic therapy.

OBJECTIVE: To investigate the relationship between acute-phase serum amyloid A (A-SAA) and joint destruction in inflammatory arthritis. METHODS: Serum A-SAA and C-reactive protein (CRP) levels, the erythrocyte sedimentation rate (ESR), and levels of matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-3, MMP-9, MMP-13, tissue inhibitor of metalloproteinases 1 (TIMP-1), vascular endothelial growth factor (VEGF), and type I and type II collagen-generated biomarkers C2C and C1,2C were measured at 0-3 months in patients with inflammatory arthritis commencing anti-tumor necrosis factor α (anti-TNFα) therapy and were correlated with 1-year radiographic progression. The effects of A-SAA on MMP/TIMP expression on RA fibroblast-like synoviocytes (FLS), primary human chondrocytes, and RA/psoriatic arthritis synovial explant cultures were assessed using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, antibody protein arrays, and gelatin zymography. RESULTS: Serum A-SAA levels were significantly (P < 0.05) correlated with MMP-3, the MMP-3:TIMP-1 ratio, C1,2C, C2C, and VEGF. The baseline A-SAA level but not the ESR or the CRP level correlated with the 28-joint swollen joint count and was independently associated with 1-year radiographic progression (P = 0.038). A-SAA increased MMP-1, MMP-3, MMP-13, and MMP/TIMP expression in RA FLS and synovial explants (P < 0.05). In chondrocytes, A-SAA induced MMP-1, MMP-3, and MMP-13 messenger RNA and protein expression (all P < 0.01), resulting in a significant shift in MMP:TIMP ratios (P < 0.05). Gelatin zymography revealed that A-SAA induced MMP-2 and MMP-9 activity. Blockade of the A-SAA receptor SR-B1 (A-SAA receptor scavenger receptor-class B type 1) inhibited MMP-3, MMP-2, and MMP-9 expression in synovial explant cultures ex vivo. Importantly, we demonstrated that A-SAA has the ability to induce TNFα expression in RA synovial explant cultures (P < 0.05). CONCLUSION: A-SAA may be involved in joint destruction though MMP induction and collagen cleavage in vivo. The ability of A-SAA to regulate TNFα suggests that A-SAA signaling pathways may provide new therapeutic strategies for the treatment of inflammatory arthritis.

Differential expression of NK receptors CD94 and NKG2A by T cells in rheumatoid arthritis patients in remission compared to active disease.

OBJECTIVE: TNF inhibitors (TNFi) have revolutionised the treatment of rheumatoid arthritis (RA). Natural killer (NK) cells and Natural Killer Cell Receptor+ T (NKT) cells comprise important effector lymphocytes whose activity is tightly regulated through surface NK receptors (NKRs). Dysregulation of NKRs in patients with autoimmune diseases has been shown, however little is known regarding NKRs expression in patients with TNFi-induced remission and in those who maintain remission vs disease flare following TNFi withdrawal. METHODS: Patients with RA were recruited for this study, (i) RA patients in clinical remission following a minimum of one year of TNFi therapy (n = -15); (2) Active RA patients, not currently or ever receiving TNFi (n = 18); and healthy control volunteers (n = 15). Patients in remission were divided into two groups: those who were maintained on TNFi and those who withdrew from TNFi and maintained on DMARDS. All patients underwent full clinical assessment. Peripheral blood mononuclear cells were isolated and NKR (CD94, NKG2A, CD161, CD69, CD57, CD158a, CD158b) expression on T-(CD3+CD56-), NK-(CD3-CD56+) and NKT-(CD3+CD56+) cells was determined by flow cytometry. RESULTS: Following TNFi withdrawal, percentages and numbers of circulating T cells, NK cells or NKT cell populations were unchanged in patients in remission versus active RA or HCs. Expression of the NKRs CD161, CD57, CD94 and NKG2A was significantly increased on CD3+CD56-T cells from patients in remission compared to active RA (p<0.05). CD3+CD56-T cell expression of CD94 and NKG2A was significantly increased in patients who remained in remission compared with patients whose disease flared (p<0.05), with no differences observed for CD161 and CD57. CD3+CD56- cell expression of NKG2A was inversely related to DAS28 (r = -0.612, p<0.005). CONCLUSION: High CD94/NKG2A expression by T cells was demonstrated in remission patients following TNFi therapy compared to active RA, while low CD94/NKG2A were associated with disease flare following withdrawal of therapy.

The impact of a revised EQ-5D population scoring on preference-based utility scores in an inflammatory arthritis cohort.

BACKGROUND AND OBJECTIVE: It is well established that there are problems with the EQ-5D. This is due to the original scoring methods used and how negative time trade-off (TTO) values were treated. A revised scoring method has been published. This article applies this to an inflammatory arthritis cohort. The objective is to examine the impact of a revised scoring system for the EQ-5D (UK) TTO on the utility estimates and in the case of rheumatoid arthritis, to explore the impact of using different utility metrics on the incremental cost-effectiveness ratio (ICER) results of an economic model. METHODS: A total of 504 patients with inflammatory arthritis were rescored using revised EQ-5D scoring, which uses an episodic random utility model to deal with negative TTO values. Differences in utility scores were compared and the new mapping coefficients were obtained. These were then used in an economic model to examine the impact on the ICER. RESULTS: In rheumatoid arthritis, the overall change is less for the revised EQ-5D scoring than with the original EQ-5D (TTO) but greater than the SF-6D: EQ-5D UK -0.22 (95% confidence interval [CI] -0.30 to -0.15), revised EQ-5D UK -0.16 (95% CI -0.21 to -0.10) and SF-6D -0.08 (95% CI -0.11 to -0.05). A similar trend is seen in the psoriatic arthritis group. The economic model produced different ICERs, when different utility measures were used; EQ-5D (TTO) €42,402, SF-6D €111,788, and revised EQ-5D (TTO) €57,747. CONCLUSION: In the context of inflammatory arthritis, this article demonstrates that a revised scoring for EQ-5D may have a significant impact on utility estimates and on the output of the economic model.

Change in CD3 positive T-cell expression in psoriatic arthritis synovium correlates with change in DAS28 and magnetic resonance imaging synovitis scores following initiation of biologic therapy--a single centre, open-label study.

INTRODUCTION: With the development of increasing numbers of potential therapeutic agents in inflammatory disease comes the need for effective biomarkers to help screen for drug efficacy and optimal dosing regimens early in the clinical trial process. This need has been recognized by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) group, which has established guidelines for biomarker validation. To seek a candidate synovial biomarker of treatment response in psoriatic arthritis (PsA), we determined whether changes in immunohistochemical markers of synovial inflammation correlate with changes in disease activity scores assessing 28 joints (ΔDAS28) or magnetic resonance imaging synovitis scores (ΔMRI) in patients with PsA treated with a biologic agent. METHODS: Twenty-five consecutive patients with PsA underwent arthroscopic synovial biopsies and MRI scans of an inflamed knee joint at baseline and 12 weeks after starting treatment with either anakinra (first 10 patients) or etanercept (subsequent 15 patients) in two sequential studies of identical design. DAS28 scores were measured at both time points. Immunohistochemical staining for CD3, CD68 and Factor VIII (FVIII) was performed on synovial samples and scored by digital image analysis (DIA). MRI scans performed at baseline and at 12 weeks were scored for synovitis semi-quantitatively. The ΔDAS28 of the European League Against Rheumatism good response definition (>1.2) was chosen to divide patients into responder and non-responder groups. Differences between groups (Mann Whitney U test) and correlations between ΔDAS28 with change in immunohistochemical and MRI synovitis scores (Spearman's rho test) were calculated. RESULTS: Paired synovial samples and MRI scans were available for 21 patients (8 anakinra, 13 etanercept) and 23 patients (8 anakinra, 15 etanercept) respectively. Change in CD3 (ΔCD3) and CD68 expression in the synovial sublining layer (ΔCD68sl) was significantly greater in the disease responders compared to non-responders following treatment (P = 0.005 and 0.013 respectively). ΔCD3, but not ΔCD68 or ΔFVIII, correlated with both ΔDAS28 (r = 0.49, P = 0.025) and ΔMRI (r = 0.58, P = 0.009). CONCLUSIONS: The correlation of ΔCD3 with ΔDAS28 and ΔMRI following biologic treatment in this cohort contributes to the validation of ΔCD3 as a synovial biomarker of disease response in PsA, and supports the further evaluation of ΔCD3 for predictive properties of future clinical outcomes.

CCR5 blockade in rheumatoid arthritis: a randomised, double-blind, placebo-controlled clinical trial.

OBJECTIVE: C-C chemokine receptor type 5 (CCR5), a chemokine receptor expressed on T cells and macrophages, and its ligands are found in inflamed synovial tissue (ST) of patients with rheumatoid arthritis (RA). The rationale for testing CCR5 blockade in patients with RA was supported by the effects of a CCR5 antagonist in collagen-induced arthritis in rhesus monkeys. The effects of CCR5 blockade in patients with active RA were explored. METHODS: In this phase Ib randomised, placebo-controlled trial, treatment with an oral CCR5 inhibitor (SCH351125) in patients with active RA was evaluated. Clinical efficacy was assessed using European League Against Rheumatism and American College of Rheumatology response criteria. ST biopsies were taken before and after 28 days of treatment, and analysed for CCR5+ cells. In a subset of patients, MRIs of an inflamed joint were obtained before and after treatment. RESULTS: In all, 32 patients were included; 20 received SCH351125 and 12 placebo. Three patients who received SCH351125 did not complete the study due to adverse events; none of these were serious. No improvement was observed in the active treatment group compared to placebo. Results were consistent for clinical evaluation, ST analysis and MRI. CONCLUSION: This proof of concept study does not support the use of CCR5 blockade as a therapeutic strategy in patients with active RA.

Fatigue is an independent outcome measure and is sensitive to change in patients with psoriatic arthritis.

OBJECTIVES: This pilot study examined sensitivity to change and relative independence of fatigue as an outcome measure in patients with psoriatic arthritis (PsA) following anti-TNF therapy. METHODS: Patients with PsA commencing anti-TNF therapy were evaluated at baseline and at 3 months. Fatigue was measured using a 0-10 numeric rating scale (NRS). This was a one-dimensional 11-point NRS with anchors of 0 (none) and 10 (a great deal). The words 'none' and 'a great deal' were placed under the NRS corresponding to the anchors 0 and 10, respectively. Sensitivity to change of fatigue was compared with recognised core outcomes and determined by calculating the standardised response means. Multiple regression analysis was employed to determine predictors of fatigue and their independent variance. RESULTS: Forty-one patients were evaluated. Mean (SD) fatigue levels were 5.6 (2.3) and 3.6 (2.2) (p=0.001) at baseline and at 3-months, respectively. Using the SRM, fatigue ranked sixth relative to the other measures demonstrating a moderate sensitivity to change. Noteworthy was the observation that fatigue was ranked higher than CRP. The relative independent variance in fatigue of 27% was greater than that of the core clinical measures: HAQ 21%, TJC 14%, Pain 4%, SJC 0.4%, GH 0.4%, and less than that of the laboratory measure CRP 33%. CONCLUSIONS: This study demonstrated that fatigue is an independent outcome measure and is sensitive to change in patients with PsA.

Remission in psoriatic arthritis: is it possible and how can it be predicted?

INTRODUCTION: Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFalpha) therapy and to examine possible predictors of response. METHODS: Analysis of a prospective patient cohort attending a biologic clinic, between November 2004 and March 2008, was performed prior to commencing therapy and at regular intervals. Baseline clinical characteristics including demographics, previous disease-modifying antirheumatic drug (DMARD) response, tender and swollen joint counts, early morning stiffness, pain visual analogue score, patient global assessment, C reactive protein (CRP) and health assessment questionnaire (HAQ) were collected. RESULTS: A total of 473 patients (152 PsA; 321 rheumatoid arthritis (RA)) were analyzed. At 12 months remission, defined according to the disease activity score using 28 joint count and CRP (DAS28-CRP), was achieved in 58% of PsA patients compared to 44% of RA patients, significant improvement in outcome measures were noted in both groups (P<0.05). Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission. Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients (P<0.001). CONCLUSIONS: DAS28 remission is possible in PsA patients at one year following anti-TNF therapy, at higher rates than in RA patients and is predicted by baseline HAQ.

Understanding the relationship between the EQ-5D, SF-6D, HAQ and disease activity in inflammatory arthritis.

BACKGROUND: The growth of economic analyses and in particular cost-utility analyses (CUA), which use the QALY as a measure of outcome, has heightened the interest in the methodologies used to calculate the QALY. The EQ-5D has produced quite different utility values from that of the SF-6D. This article seeks to understand these differences using a cohort of patients with inflammatory arthritis. OBJECTIVE: To examine the relationship between the disease-specific measure, Health Assessment Questionnaire (HAQ) disability index (DI) and the preference-based measures, SF-6D, EQ-5D and European League Against Arthritis (EULAR) Disease Activity Score (DAS) in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: Patients with RA and PsA (n = 504) attending a tertiary rheumatology referral centre completed the HAQ, SF-6D and the EQ-5D before starting biological therapy and again 12 months later. The SF-36 was converted into a utility using the preference-based SF-6D. Clinical outcomes such as the DAS, joint counts and laboratory measures were also recorded. We calculated single index utility scores from the preference-based instruments using UK population norms. We used regression analysis to derive a mapping function and calculated utility scores from the HAQDI and the DAS 28. RESULTS: The mean utility observed at baseline for RA was 0.43 for the EQ-5D and 0.54 for the SF-6D and for PsA was 0.49 for the EQ-5D and 0.57 for the SF-6D. The utility gain demonstrated by the EQ-5D was over twice that of the SF-6D. The EQ-5D scored 17% of the RA group as less than 0 (state defined as worse than death); 7% of this group remained less than 0 at follow-up. The distribution of the utility estimates was similar for both RA and PsA. CONCLUSIONS: Our findings draw attention to the impact of states worse than death on the overall distribution for the EQ-5D derived utilities and how these impact on its use in practice. EQ-5D-derived QALY changes are over twice that of the SF-6D. The implication of this for decision makers is that cost-effectiveness evaluations for treatments in this disease class are likely to be very sensitive to the choice of utility measure.

Acute serum amyloid A induces migration, angiogenesis, and inflammation in synovial cells in vitro and in a human rheumatoid arthritis/SCID mouse chimera model.

Serum amyloid A (A-SAA), an acute-phase protein with cytokine-like properties, is expressed at sites of inflammation. This study investigated the effects of A-SAA on chemokine-regulated migration and angiogenesis using rheumatoid arthritis (RA) cells and whole-tissue explants in vitro, ex vivo, and in vivo. A-SAA levels were measured by real-time PCR and ELISA. IL-8 and MCP-1 expression was examined in RA synovial fibroblasts, human microvascular endothelial cells, and RA synovial explants by ELISA. Neutrophil transendothelial cell migration, cell adhesion, invasion, and migration were examined using transwell leukocyte/monocyte migration assays, invasion assays, and adhesion assays with or without anti-MCP-1/anti-IL-8. NF-kappaB was examined using a specific inhibitor and Western blotting. An RA synovial/SCID mouse chimera model was used to examine the effects of A-SAA on cell migration, proliferation, and angiogenesis in vivo. High expression of A-SAA was demonstrated in RA patients (p < 0.05). A-SAA induced chemokine expression in a time- and dose-dependent manner (p < 0.05). Blockade with anti-scavenger receptor class B member 1 and lipoxin A4 (A-SAA receptors) significantly reduced chemokine expression in RA synovial tissue explants (p < 0.05). A-SAA induced cell invasion, neutrophil-transendothelial cell migration, monocyte migration, and adhesion (all p < 0.05), effects that were blocked by anti-IL-8 or anti-MCP-1. A-SAA-induced chemokine expression was mediated through NF-kappaB in RA explants (p < 0.05). Finally, in the RA synovial/SCID mouse chimera model, we demonstrated for the first time in vivo that A-SAA directly induces monocyte migration from the murine circulation into RA synovial grafts, synovial cell proliferation, and angiogenesis (p < 0.05). A-SAA promotes cell migrational mechanisms and angiogenesis critical to RA pathogenesis.

A role for the high-density lipoprotein receptor SR-B1 in synovial inflammation via serum amyloid-A.

Acute phase apoprotein Serum Amyloid A (A-SAA), which is strongly expressed in rheumatoid arthritis synovial membrane (RA SM), induces angiogenesis, adhesion molecule expression, and matrix metalloproteinase production through the G-coupled receptor FPRL-1. Here we report alternative signaling through the high-density lipoprotein receptor scavenger receptor-class B type 1 (SR-B1). Quantitative expression/localization of SR-B1 in RA SM, RA fibroblast-like cells (FLCs), and microvascular endothelial cells (ECs) was assessed by Western blotting and immunohistology/fluorescence. A-SAA-mediated effects were examined using a specific antibody against SR-B1 or amphipathic alpha-Helical Peptides (the SR-B1 antagonists L-37pA and D-37pA), in RA FLCs and ECs. Adhesion molecule expression and cytokine production were quantified using flow cytometry and ELISA. SR-B1 was strongly expressed in the RA SM lining layer and endothelial/perivascular regions compared with osteoarthritis SM or normal control synovium. Differential SR-B1 expression in RA FLC lines (n = 5) and ECs correlated closely with A-SAA, but not tumor necrosis factor alpha-induced intercellular adhesion molecule-1 upregulation. A-SAA-induced interleukin-6 and -8 production was inhibited in the presence of anti-SR-B1 in human microvascular endothelial cells and RA FLCs. Moreover, D-37pA and L-37pA inhibited A-SAA-induced vascular cell adhesion molecule-1 and intercellular adhesion molecule expression from ECs in a dose-dependent manner. As SR-B1 is expressed in RA synovial tissue and mediates A-SAA-induced pro-inflammatory pathways, a better understanding of A-SAA-mediated inflammatory pathways may lead to novel treatment strategies for RA.

Synovial tissue rank ligand expression and radiographic progression in rheumatoid arthritis: observations from a proof-of-concept randomized clinical trial of cytokine blockade.

The objective of the study was to evaluate synovial tissue receptor activator of nuclear factor-κß ligand (RANKL) and osteoprotegerin (OPG) as biomarkers of disease activity, progressive joint damage, and therapeutic response, during cytokine blockade in rheumatoid arthritis (RA). Patients with active RA entered a randomized open-label 12-month study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 µg/kg twice weekly. Arthroscopic synovial tissue biopsies were obtained at baseline, at 4 weeks and at the final time point. Following immunohistochemical staining, RANKL and OPG expression was quantified using digital image analysis. Radiographic damage was evaluated using the van der Heijde modification of the Sharp scoring system. Twenty-two patients were randomized. Baseline expression of RANKL, but not OPG, correlated significantly with baseline CRP levels (r = 0.61, P < 0.01). While a significant reduction in OPG expression following treatment was observed in clinical responders at the final time point (P < 0.05 vs. baseline), RANKL levels did not change, and the RANKL:OPG ratio remained unaltered, even at the highest levels of clinical response. When potential predictors of radiographic outcome were evaluated, baseline RANKL expression correlated with erosive progression at 1 year (r = 0.71, P < 0.01). Distinct, though related, pathophysiologic processes mediate joint inflammation and destruction in RA. Elevated synovial tissue RANKL expression is associated with progressive joint erosion, and may be independent of the clinical response to targeted therapy. The potential therapeutic importance of modulating RANKL in RA is highlighted, if radiographic arrest is to be achieved.

Synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression: analysis of a proof-of-concept randomised clinical trial of cytokine blockade.

OBJECTIVES: To evaluate synovial tissue and serum biomarkers of disease activity, therapeutic response and radiographic progression during biological therapy for rheumatoid arthritis (RA). METHODS: Patients with active RA entered a randomised study of anakinra 100 mg/day, administered as monotherapy or in combination with pegsunercept 800 microg/kg twice a week. Arthroscopic synovial tissue biopsies were obtained at baseline and two further time points. Following immunohistochemical staining, selected mediators of RA pathophysiology were quantified using digital image analysis. Selected mediators were also measured in the serum. RESULTS: Twenty-two patients were randomly assigned: 11 received monotherapy and 11 combination therapy. American College of Rheumatology 20, 50 and 70 response rates were 64%, 64% and 46% with combination therapy and 36%, 9% and 0% with monotherapy, respectively. In synovial tissue, T-cell infiltration, vascularity and transforming growth factor beta (TGFbeta) expression demonstrated significant utility as biomarkers of disease activity and therapeutic response. In serum, interleukin 6 (IL-6), matrix metalloproteinase (MMP) 1, MMP-3 and tissue inhibitor of metalloproteinase 1 (TIMP-1) were most useful in this regard. An early decrease in serum levels of TIMP-1 was predictive of the later therapeutic outcome. Pretreatment tissue levels of T-cell infiltration and the growth factors vascular endothelial growth factor/TGFbeta, and serum levels of IL-6, IL-8, MMP-1, TIMP-1, soluble tumour necrosis factor receptor types I and II and IL-18 correlated with radiographic progression. CONCLUSIONS: Synovial tissue analysis identified biomarkers of disease activity, therapeutic response and radiographic progression. Biomarker expression in tissue was independent of the levels measured in the serum.

Fatigue is a reliable, sensitive and unique outcome measure in rheumatoid arthritis.

OBJECTIVE: Fatigue is an important symptom in patients with RA. Measurement of fatigue in clinical trials and in clinical practice requires scales that are reproducible, sensitive to change and practical. This study examined the reliability and sensitivity to change of fatigue and its relative independence as an outcome measure in RA. METHODS: Successive patients referred to the rheumatology clinic at St Vincent's University Hospital and Our Lady's Hospice were evaluated. Clinical assessments were undertaken at baseline and 3 months after commencing TNF-alpha blockade. Fatigue was measured using an 11-point numeric rating scale (NRS). Sensitivity to change when compared with current core set outcome measures was determined by calculation of the standardized response mean (SRM). Multiple regression analysis was employed to determine the independent variance of fatigue scores relative to the core set. RESULTS: Forty-nine patients were evaluated. At baseline, mean (s.d.) fatigue scores were 6.7 +/- 2.1. At 3 months, fatigue scores had fallen to 4.3 +/- 2.6 (P < 0.001). Test-retest intraclass correlation coefficient for the NRS was 0.79 (P < 0.008). Fatigue was ranked third for relative sensitivity to change as shown by SRM: pain, 1.37; tender joint count (TJC), 1.09; fatigue, 0.92; swollen joint count (SJC), 0.86; HAQ, 0.82; CRP, 0.69; and patient global health (GH), 0.25. The relative independent variance in fatigue of 22% was higher than that of the core set: TJC, 20%; pain, 19%; SJC, 16%; GH, 8%; HAQ, 7%; and CRP, 8%. CONCLUSIONS: This study demonstrates that measures of fatigue are reliable and sensitive to change, and should be considered for inclusion as a core outcome measure in RA.

Assessing quality of sleep in patients with rheumatoid arthritis.

We sought to identify instruments assessing sleep quality that measure the domains of sleep applicable to rheumatoid arthritis (RA) patients and are feasible to use and have appropriate reliability, validity, and responsiveness properties. A systematic review of sleep instruments was conducted. In particular, domains related to sleep that were assessed in the instruments were identified and evaluated. Feasibility characteristics and psychometric properties of instruments were reviewed. At OMERACT 9, the preparatory work was described at the plenary session of the Patient Perspective Workshop, and the tasks of 3 breakout groups in ranking and scoring the domains and sleep instruments were outlined. Each breakout group considered different aspects of sleep: sleep domains, feasibility, and psychometric properties. The rapporteur for each breakout group reported back to the plenary on the domains and sleep instruments that achieved the highest rank/score. The systematic review identified 45 sleep instruments of interest. Based on these instruments, 14 domains of sleep were identified. The top ranked domains were: Sleep Adequacy (1), Sleep Maintenance (2), Sleep Initiation (3) and Daytime Functioning (4). The top ranked instruments on feasibility were: Athens Insomnia Scale (2.3), Medical Outcome Study (MOS) Sleep (4.0), Insomnia Severity Index (4.9), and Women's Health Insomnia Rating Scale (5.5). The highest scored instruments on psychometric properties were: Athens Insomnia Scale (13.6), Sleep Assessment Questionnaire (13), Pittsburgh Sleep Diary (12), and MOS Sleep (11). Sleep domains have been reviewed, and several sleep instruments have been identified. These instruments should be considered for use in planned clinical trials of RA patients to assess their applicability.

Synovial tissue sublining CD68 expression is a biomarker of therapeutic response in rheumatoid arthritis clinical trials: consistency across centers.

OBJECTIVE: To determine whether the correlation between the mean change in disease activity and the mean change in synovial sublining (sl) CD68 expression could be demonstrated across different academic centers. METHODS: Synovial biopsies obtained at arthroscopy from patients with rheumatoid arthritis before and 160 days after rituximab therapy were selected and coded. Paired sections were processed independently at Amsterdam Medical Center (AMC) and at St. Vincent's University Hospital (SVUH), Dublin. Digital image analysis (DIA) was employed at both centers to quantify sublining CD68 expression. RESULTS: After analysis of CD68sl expression at centers in 2 different countries, high levels of intracenter and intercenter agreement were observed. For the pooled sections stained at AMC, the correlation between 2 investigators was R = 0.942, p = 0.000, and for sections stained at SVUH, R = 0.899, p = 0.001. Similarly, the intracenter correlations for DeltaCD68sl expression after treatment were R = 0.998, p = 0.000, for sections stained at AMC and R = 0.880, p = 0.000, for sections stained at SVUH. The intercenter correlation for the pooled scores of sections stained at AMC was R = 0.85, p = 0.000, and for the sections stained at SVUH, R = 0.62, p = 0.001. The consistent correlation between DeltaDAS (Disease Activity Score) and DeltaCD68sl expression across different studies (Pearson correlation = 0.895, p < 0.001) was confirmed. The standardized response mean values for DeltaCD68sl, calculated from analyses at both AMC and SVUH, were consistently 0.5 or greater, indicating a moderate to high potential to detect change. CONCLUSION: The correlation between mean DeltaDAS and mean DeltaCD68sl expression was confirmed across 2 centers. Examination of serial biopsy samples can be used reliably to screen for interesting biological effects at the site of inflammation at an early stage of drug development.

Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-alpha, Oncostatin M and response to biologic therapies.

INTRODUCTION: The aim of this study was to examine IL-17A in patients, following anti-TNF-alpha therapy and the effect of IL-17A on matrix turnover and cartilage degradation. METHODS: IL-17A expression was examined by ELISA and immunohistology in the rheumatoid arthritis (RA) joints. RA whole synovial tissue explant (RA ST), primary synovial fibroblasts (RASFC), human cartilage and chondrocyte cultures were stimulated with IL-17A +/- TNF-alpha and Oncostatin M (OSM). Matrix metalloproteinase (MMP) and tissue inhibitor (TIMP-1) were assessed by ELISA and zymography. Cartilage proteoglycan release was assessed histologically by Safranin-O staining. Clinical parameters, IL-17A, MMP/TIMP were assessed in patients pre/post biologic therapy. RESULTS: IL-17A levels were higher in RA vs osteoarthritis (OA)/normal joints (P < 0.05). IL-17A up-regulated MMP-1, -2, -9, and -13 in RA ST, RASFC, cartilage and chondrocyte cultures (P < 0.05). In combination with TNF-alpha and OSM, IL-17A shifted the MMP:TIMP-1 ratio in favor of matrix degradation (all P < 0.05). Cartilage proteoglycan depletion in response to IL-17A was mild; however, in combination with TNF-alpha or OSM showed almost complete proteoglycan depletion. Serum IL-17A was detected in 28% of patients commencing biologic therapy. IL-17A negative patients demonstrated reductions post therapy in serum MMP1/TIMP4, MMP3/TIMP1 and MMP3/TIMP4 ratios and an increase in CS846 (all P < 0.05). No significant changes were observed in IL-17A positive patients. CONCLUSIONS: IL-17A is produced locally in the inflamed RA joint. IL-17A promotes matrix turnover and cartilage destruction, especially in the presence of other cytokines, mimicking the joint environment. IL-17A levels are modulated in vivo, following anti-TNF therapy, and may reflect changes in matrix turnover.