Showing papers in "Annals of the Rheumatic Diseases in 2007"

Changes in causes of death in systemic sclerosis, 1972-2002.

Abstract: Background: Survival of scleroderma has changed since the renal crisis treatment has become possible. Aims: To document the changes in survival and organ system causes of mortality in systemic sclerosis (SSc) over the past 25 years in patients from a single medical centre. Methods: Consecutive patients evaluated at the University of Pittsburgh, Pittsburgh, Pennsylvania, USA between 1 January 1972 and 31 December 1996 were studied. Survival was determined in five 5-year time periods between 1972 and 1997. Causes of death included scleroderma-related (scleroderma renal crisis, pulmonary arterial hypertension, pulmonary fibrosis (PF), gastrointestinal (GI), heart and multiorgan failure) and non-scleroderma-related (cancer, atherosclerotic cardiovascular or cerebrovascular disease, infection, sudden death, other and unknown) causes. Results: The 10-year survival improved steadily from 54% to 66% during each of the time intervals. There was a significant improvement in survival for patients during 1982–91 compared with those during 1972–81 (p Conclusion: The change in the pattern of scleroderma-related deaths over the past 30 years demonstrates that the lung (both pulmonary hypertension and PF) is the primary cause of scleroderma-related deaths today. It is important that aggressive searches continue to develop better therapies for these severe pulmonary complications of SSc.

Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database

Abstract: Background: Systemic sclerosis (SSc) is a multisystem autoimmune disease which is classified into a diffuse cutaneous (dcSSc) and a limited cutaneous (lcSSc) subset according to the skin involvement. In order to better understand the vascular, immunological and fibrotic processes of SSc and to guide its treatment the EULAR Scleroderma Trials And Research (EUSTAR) group was formed in June 2004. Aims and Methods: EUSTAR collects prospectively the Minimal Essential Data Set (MEDS) on all sequential patients fulfilling the ACR diagnostic criteria in participating centres. We aimed to characterize demographic, clinical and laboratory characteristics of disease presentation in SSc and analysed EUSTAR baseline visits. Results: In April 2006, a total of 3656 patients (1349 with dcSSc and 2101 with lcSSc) were enrolled in 102 centres and 30 countries. 1330 individuals had autoantibodies against Scl70 and 1106 against anticentromere antibodies. 87% of patients were female. On multivariate analysis, scleroderma subsets (dcSSc vs. lcSSc), antibody status and age at onset of Raynaud’s phenomenon, but not gender were independently associated with the prevalence of organ manifestations. Autoantibody status in this analysis appeared more closely associated with clinical manifestations than were SSc subsets. Conclusion: dcSSc and lcSSc subsets are associated with particular organ manifestations, but in this analysis the clinical distinction appeared superseded by an antibody based classification in predicting some scleroderma complications. The EUSTAR MEDS data base facilitates the analysis of clinical patterns in SSc and contributes to the standardised assessment and monitoring of SSc internationally.

EULAR evidence based recommendations for the management of fibromyalgia syndrome

Abstract: Objective: To develop evidence-based recommendations for the management of fibromyalgia syndrome. Methods: A multidisciplinary task force was formed representing 11 European countries. The design o ...

Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab

Abstract: Objective To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA. Methods In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of Results Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p Conclusion Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.

Vitamin D and autoimmunity: new aetiological and therapeutic considerations

Abstract: Vitamin D is frequently prescribed by rheumatologists to prevent and treat osteoporosis. Several observations have shown that vitamin D inhibits proinflammatory processes by suppressing the enhanced activity of immune cells that take part in the autoimmune reaction. Moreover, recent evidence strongly suggests that vitamin D supplementation may be therapeutically beneficial, particularly for Th1-mediated autoimmune disorders. Some reports imply that vitamin D may even be preventive in certain disorders such as multiple sclerosis and diabetes type 1. It seems that vitamin D has crossed the boundaries of calcium metabolism and has become a significant factor in a number of physiological functions, specifically as a biological inhibitor of inflammatory hyperactivity.

Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial)

Abstract: BACKGROUND: To investigate whether intensive treatment with methotrexate (MTX) according to a strict protocol and a computerised decision program is more beneficial compared to conventional treatment with MTX in early rheumatoid arthritis. METHODS: In a two-year multicentre open label strategy trial, 299 patients with early rheumatoid arthritis were randomly assigned to the intensive strategy group or the conventional strategy group. Patients in both groups received MTX, the aim of treatment being remission. Patients in the intensive treatment group came to the outpatient clinic once every month; adjustment of the MTX dosage was tailored to the individual patient on the basis of predefined response criteria, using a computerised decision program. Patients of the conventional strategy group came to the outpatient clinic once every three months; they were treated according to common practice. Cyclosporine was added if patients had an inadequate response to maximal tolerated MTX doses. RESULTS: Seventy six (50%) patients in the intensive strategy group achieved at least one period of remission during the two year trial, versus 55 patients (37%) in the conventional strategy group (p = 0.03). Areas under the curve for nearly all clinical variables were significantly lower-that is, there was a better clinical effect for the intensive treatment group compared with the conventional treatment group. CONCLUSION: The results of this study show that it is possible to substantially enhance the clinical efficacy early in the course of the disease by intensifying treatment with MTX, aiming for remission, tailored to the individual patient. Furthermore, participating rheumatologists indicated that the computerised decision program could be a helpful tool in their daily clinical practice.

EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis

Abstract: Objectives: To develop the European League Against Rheumatism (EULAR) recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis. Methods: An expert consensus group was formed consisting of rheumatologists, nephrologists and specialists in internal medicine representing five European countries and the USA, a clinical epidemiologist and representatives from regulatory agencies. Using an evidence-based and expert opinion-based approach in accordance with the standardised EULAR operating procedures, the group identified nine topics for a systematic literature search through a modified Delphi technique. On the basis of research questions posed by the group, recommendations were derived for conducting clinical studies and/or clinical trials in systemic vasculitis. Results: Based on the results of the literature research, the expert committee concluded that sufficient evidence to formulate guidelines on conducting clinical trials was available only for anti-neutrophil cytoplasm antibody-associated vasculitides (AAV). It was therefore decided to focus the recommendations on these diseases. Recommendations for conducting clinical trials in AAV were elaborated and are presented in this summary document. It was decided to consider vasculitis-specific issues rather than general issues of trial methodology. The recommendations deal with the following areas related to clinical studies of vasculitis: definitions of disease, activity states, outcome measures, eligibility criteria, trial design including relevant end points, and biomarkers. A number of aspects of trial methodology were deemed important for future research. Conclusions: On the basis of expert opinion, recommendations for conducting clinical trials in AAV were formulated. Furthermore, the expert committee identified a strong need for well-designed research in non-AAV systemic vasculitides.

Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis

Abstract: Background: A substantial proportion of patients with rheumatoid arthritis (RA) do not respond, or lose initial response, to adalimumab treatment. One explanation for non-response is that patients develop anti-adalimumab antibodies. Objectives: To evaluate the incidence of formation of antibody against adalimumab and the association with serum adalimumab concentrations and clinical response. Methods: In a cohort of 121 consecutive patients with RA treated with adalimumab, serum adalimumab concentrations and antibodies against adalimumab were measured together with clinical response variables before and up to 28 weeks after the start of treatment. Results: Anti-adalimumab antibodies were detected in 21 patients (17%) during 28 weeks of treatment. EULAR non-responders had antibodies significantly more often than good responders (34% vs 5%; p = 0.032). Patients with antibodies showed less improvement in disease activity (mean (SD) delta DAS28 0.65 (1.35)) than patients without antibodies (mean delta DAS28 1.70 (1.35)) (p = 0.001). Patients with antibodies during follow-up had lower serum adalimumab concentrations at 28 weeks than patients without antibodies (median 1.2 mg/l, range 0.0–5.6 vs median 11.0 mg/l, range 2.0–33.0, respectively; p Conclusions: Serum antibodies against adalimumab are associated with lower serum adalimumab concentrations and non-response to adalimumab treatment.

Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis

Abstract: Objective: To examine the relationship between longitudinal fluctuations in synovitis with change in pain and cartilage in knee osteoarthritis. Methods: Study subjects were patients 45 years of age and older with symptomatic knee osteoarthritis from the Boston Osteoarthritis of the Knee Study. Baseline and follow-up assessments at 15 and 30 months included knee magnetic resonance imaging (MRI), BMI and pain assessment (VAS) over the last week. Synovitis was scored at 3 locations (infrapatellar fat pad, suprapatellar and intercondylar regions) using a semiquantitative scale (0–3) at all 3 time points on MRI. Scores at each site were added to give a summary synovitis score (0–9). Results: We assessed 270 subjects whose mean (SD) age was 66.7 (9.2) years, BMI 31.5 (5.7) kg/m 2 ; 42% were female. There was no correlation of baseline synovitis with baseline pain score (r = 0.09, p = 0.17). The change in summary synovitis score was correlated with the change in pain (r = 0.21, p = 0.0003). An increase of one unit in summary synovitis score resulted in a 3.15-mm increase in VAS pain score (0–100 scale). Effusion change was not associated with pain change. Of the 3 locations for synovitis, changes in the infrapatellar fat pad were most strongly related to pain change. Despite cartilage loss occurring in over 50% of knees, synovitis was not associated with cartilage loss in either tibiofemoral or patellofemoral compartment. Conclusions: Change in synovitis was correlated with change in knee pain, but not loss of cartilage. Treatment of pain in knee osteoarthritis (OA) needs to consider treatment of synovitis.

Effect of hydroxychloroquine on the survival of patients with systemic lupus erythematosus: data from LUMINA, a multiethnic US cohort (LUMINA L)

Abstract: Objective: In patients with systemic lupus erythematosus (SLE), hydroxychloroquine prevents disease flares and damage accrual and facilitates the response to mycophenolate mofetil in those with renal involvement. A study was undertaken to determine whether hydroxychloroquine also exerts a protective effect on survival. Methods: Patients with SLE from the multiethnic LUMINA (LUpus in MInorities: NAture vs nurture) cohort were studied. A case-control study was performed within the context of this cohort in which deceased patients (cases) were matched for disease duration (within 6 months) with alive patients (controls) in a proportion of 3:1. Survival was the outcome of interest. Propensity scores were derived by logistic regression to adjust for confounding by indication as patients with SLE with milder disease manifestations are more likely to be prescribed hydroxychloroquine. A conditional logistic regression model was used to estimate the risk of death and hydroxychloroquine use with and without the propensity score as the adjustment variable. Results: There were 608 patients, of whom 61 had died (cases). Hydroxychloroquine had a protective effect on survival (OR 0.128 (95% CI 0.054 to 0.301 for hydroxychloroquine alone and OR 0.319 (95% CI 0.118 to 0.864) after adding the propensity score). As expected, the propensity score itself was also protective. Conclusions: Hydroxychloroquine, which overall is well tolerated by patients with SLE, has a protective effect on survival which is evident even after taking into consideration the factors associated with treatment decisions. This information is of importance to all clinicians involved in the care of patients with SLE.

Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France

Abstract: Background: Anakinra treatment has been reported to be effective in some patients with systemic-onset juvenile idiopathic arthritis (SoJIA) or adult-onset Still disease (AoSD). Objectives: To assess the efficacy and the safety of anakinra treatment in SoJIA and AoSD. Methods: SoJIA and AoSD patients were treated with anakinra (1–2 mg/kg/day in children, 100 mg/day in adults); we analysed its effect on fever, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, numbers of swollen and tender joints, the assessment of disease activity (by physician and parent/patient) and pain (by parent/patient), and American College of Rheumatology (ACR) pediatric core set criteria for JIA activity. Results: A total of 35 patients were included, 20 with SoJIA and 15 with AoSD. Their mean age (range) at the onset of treatment was 12.4 (3–23) and 38.1 (22–62) years, respectively; disease duration was 7.0 (1–16) and 7.8 (2–27) years, respectively. Active arthritis was present in all cases but one. Of the 20 SoJIA patients, 5 achieved ACR 50% improvement in symptoms (ACR50) response criteria at 6 months. Steroid dose had been decreased by 15% to 78% in 10 cases. A total of 11 of the 15 AoSD patients achieved at least a 50% improvement for all disease markers (mean follow-up: 17.5 (11–27) months). Steroids had been stopped in two cases and the dose was decreased by 45% to 95% in 12 patients. Two patients stopped anakinra due to severe skin reaction, and two patients due to infection: one visceral leishmaniasis and one varicella. Conclusion: Anakinra was effective in most AoSD patients, but less than half SoJIA patients achieved a marked and sustained improvement.

Comparison of Disease Activity Score (DAS)28- erythrocyte sedimentation rate and DAS28- C-reactive protein threshold values

Abstract: Objective: To estimate the disease activity score (DAS)28-C-reactive protein (CRP) threshold values that correspond to DAS28-erythrocyte sedimentation rate (ESR) values for remission, low disease activity and high disease activity in patients with rheumatoid arthritis. Methods: DAS28 data were analysed using a large observational study (Institute of Rheumatology Rheumatoid Arthritis) database of 6729 patients with rheumatoid arthritis. Firstly, the relationship between the DAS28-ESR and the DAS28-CRP values was analysed. Secondly, the best DAS28-CRP trade-off values for each threshold were calculated using receiver operating characteristic (ROC) curves. Results: The correlation coefficient of ESR versus CRP was 0.686, whereas that of DAS28-ESR versus DAS28-CRP was 0.946, showing the strong linear relationship between DAS28-ESR and DAS28-CRP values. DAS28-CRP threshold values corresponding to remission, low disease activity and high disease activity were 2.3, 2.7 and 4.1, respectively. The sensitivity and specificity from the ROC curves were gradually reduced as DAS28 values became lower. Conclusions: This study showed that DAS28-CRP and DAS28-ESR were well correlated, but the threshold values should be reconsidered. As the results were derived from only Japanese patients, it is essential to compare DAS28-CRP threshold values in people of other ethnic groups.

EULAR evidence based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases.

Abstract: Objective: To develop evidence-based recommendations for the management of systemic glucocorticoid (GC) therapy in rheumatic diseases. Methods: The multidisciplinary guideline development group from 11 European countries, Canada and the USA consisted of 15 rheumatologists, 1 internist, 1 rheumatologist–epidemiologist, 1 health professional, 1 patient and 1 research fellow. The Delphi method was used to agree on 10 key propositions related to the safe use of GCs. A systematic literature search of PUBMED, EMBASE, CINAHL, and Cochrane Library was then used to identify the best available research evidence to support each of the 10 propositions. The strength of recommendation was given according to research evidence, clinical expertise and perceived patient preference. Results: The 10 propositions were generated through three Delphi rounds and included patient education, risk factors, adverse effects, concomitant therapy (ie, non-steroidal anti-inflammatory drugs, gastroprotection and cyclo-oxygenase-2 selective inhibitors, calcium and vitamin D, bisphosphonates) and special safety advice (ie, adrenal insufficiency, pregnancy, growth impairment). Conclusion: Ten key recommendations for the management of systemic GC-therapy were formulated using a combination of systematically retrieved research evidence and expert consensus. There are areas of importance that have little evidence (ie, dosing and tapering strategies, timing, risk factors and monitoring for adverse effects, perioperative GC-replacement) and need further research; therefore also a research agenda was composed.

Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis

Abstract: Background: Normal adult articular cartilage is thought to be avascular and aneural. Objective: To describe neurovascular structures at the osteochondral junction and in osteophytes in tibiofemoral osteoarthritis (OA) displaying a range of severity of cartilage changes. Methods: Articular surfaces were obtained from 40 patients at total knee joint replacement surgery for tibiofemoral OA (TKR) and seven patients post mortem (PM). Antibodies directed against CD34 (vascular endothelium), protein gene product 9.5 (pan-neuronal marker), substance P and calcitonin gene-related peptide (sensory nerves) and C-flanking peptide of neuropeptide Y (sympathetic nerves) were used to localise blood vessels and nerves by immunohistochemistry. Severity of OA cartilage changes was graded histologically. Results: TKR and PM samples displayed a range of OA cartilage changes including tidemark breaching by vascular channels. Sympathetic and sensory nerves were both present within vascular channels in the articular cartilage, in both mild and severe OA. Perivascular and free nerve fibres, and nerve trunks were observed within the subchondral bone marrow and within the marrow cavities of osteophytes. Sensory and sympathetic nerves displayed similar distributions in each region studied. Conclusion: Vascularisation and the associated innervation of articular cartilage may contribute to tibiofemoral pain in OA across a wide range of structural disease severity.

Time‐dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists

Abstract: OBJECTIVES:The degree to which treatment with tumour necrosis factor (TNF) antagonists may be associated with increased risks for serious infections is unclear. An observational cohort study was pe ...

The diagnostic utility of myositis autoantibody testing for predicting the risk of cancer-associated myositis

Abstract: Objectives: There is a known association between myositis and cancer. The risk is greater in dermatomyositis (DM) than polymyositis (PM), although reliable methods to predict cancer risk in specific patients with myositis are not presently available. This study was undertaken to determine whether risk of developing cancer in myositis can be predicted by antibody profiling. Methods: A cross-sectional study of UK Caucasian adults with PM (n = 109), DM (n = 103) and connective tissue disease overlap (myositis/CTD-overlap, n = 70). Patients were tested for a comprehensive range of myositis-specific/associated autoantibodies. Sensitivity and specificity analyses were performed for the optimal identification of cancer risk. Results: Sixteen patients had cancer-associated myositis (CAM) (15 DM, 1 myositis/CTD-overlap). CAM patients were older at disease onset, and patients without myositis-specific/associated autoantibodies on “routine” laboratory testing (negative for anti-Jo-1, anti-PM-Scl, anti-U1-RNP, anti-U3-RNP, anti-Ku antibodies) had a significantly increased risk of CAM. Possession of the antibody against 155 kDa and 140 kDa protein specificities (anti-155/140 antibody) represented a significant risk factor for CAM, and was found exclusively in DM. A positive anti-155/140 antibody result proved highly specific, moderately sensitive, with high negative predictive value for CAM. A “negative routine myositis antibody panel” result was highly sensitive, with high negative predictive value for CAM. The combination of these two approaches was 94% sensitive, detecting 15 of 16 CAM, with 100% sensitivity and negative predictive value in DM. Conclusions: These results may help clinicians predict which patients with myositis are at greater risk of developing cancer, thus identifying those requiring aggressive diagnostic evaluation and intensive cancer surveillance at myositis onset and follow-up.

Rheumatoid Arthritis subtypes identified by genomic profiling of peripheral blood cells: Assignment of a type I interferon signature in a subpopulation of patients

Abstract: Objective: Rheumatoid arthritis (RA) is a heterogeneous disease with unknown etiology. Here we aimed to identify peripheral blood gene expression profiles that may distinguish RA subtypes. Methods: Large-scale expression profiling by cDNA microarrays was performed on peripheral blood from 35 patients and 15 healthy individuals. Differential gene expression was analyzed by Significance Analysis of Microarrays (SAM), followed by Gene Ontology analysis of the significant genes. Gene Set Enrichment Analysis (GSEA) was applied to identify pathways relevant to disease. Results: We found a remarkably elevated expression of a spectrum of genes involved in immune defense in the peripheral blood of RA patients compared to healthy individuals. SAM analysis revealed a highly significant elevated expression of interferon (IFN) type I regulated genes in RA compared to healthy individuals, which was confirmed by Gene Ontology and Pathway analysis, suggesting that this pathway was activated systemically in RA. A quantitative analysis revealed that increased expression of IFN-response genes was characteristic of approximately half of the patients (IFN high patients). Application of pathway analysis revealed that the IFN high group was largely different from the controls, with evidence for upregulated pathways involved in coagulation and complement cascades, and fatty acid metabolism, while the IFNlow group was similar to the controls. Conclusion: The IFN type I signature defines a subgroup of RA patients, with a distinct biomolecular phenotype, characterized by increased activity of the innate defense system.

Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study

Abstract: Background: Juvenile idiopathic arthritis (JIA) consists of a heterogeneous group of disorders with, for the most part, an unknown immunopathogenesis. Although onset and disease course differ, the subtypes of JIA share the occurrence of chronic inflammation of the joints, with infiltrations of immunocompetent cells that secrete inflammatory mediators. Objective: To identify a panel of cytokines specifically related to the inflammatory process in JIA. Methods: Using a new technology, the multiplex immunoassay, 30 cytokines were measured in plasma of 65 patients with JIA, of which 34 were paired with synovial fluid. These data were compared with plasma of 20 healthy controls and 9 patients with type I diabetes, a chronic inflammatory disease. Results: Patients with JIA had, irrespective of their subclassification, significantly higher levels of tumour necrosis factor α, macrophage inhibitory factor (MIF), CCL2, CCL3, CCL11, CCL22 and CXCL9 in plasma than controls. In paired plasma and synovial fluid samples of patients with JIA, significantly higher levels of interleukin (IL)6, IL15, CCL2, CCL3, CXCL8, CXCL9 and CXCL10 were present in synovial fluid. Cluster analysis in all patients with JIA revealed a predominant pro-inflammatory cytokine cluster during active disease and a regulatory/anti-inflammatory-related cytokine cluster during remission. Whether a discrimination profile of various cytokines could help in the determination of disease classification was tested. Conclusion: It is suggested that several cytokines (IL18, MIF, CCL2, CCL3, CCL11, CXCL9 and CXCL10) may correspond to the activation status during inflammation in JIA and could be instrumental in monitoring disease activity and outcomes of (new) immunotherapies.

A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects

Abstract: Objective: Open label studies have suggested that tumour necrosis factor (TNF) antagonists led to sustained improvement and corticosteroid sparing effect in patients with giant cell arteritis (GCA). To confirm these observations, we conducted a randomised, double-blind, placebo controlled trial with etanercept in patients with biopsy-proven GCA with side effects secondary to corticosteroids. Methods: We randomly assigned patients with GCA to receive etanercept (n = 8) or placebo (n = 9) over 1 year together with corticosteroids that were reduced according to a predefined schedule. The primary outcome was the ability to withdraw the corticosteroid therapy and control the disease activity at 12 months. Results: Baseline characteristics were similar in the two groups, although patients in the etanercept group showed higher levels of basal glycaemia (p = 0.02) and a higher erythrocyte sedimentation rate (ESR) (p = 0.01). After 12 months, 50% of the patients in the etanercept group and 22.2% in the placebo group were able to control the disease without corticosteroid therapy (p value not significant). Patients in the etanercept group had a significant lower dose of accumulated prednisone during the first year of treatment (p = 0.03). There were no differences in the number and type of adverse events. Conclusion: The limited number of patients included in this study does not allow us to draw definitive conclusions. Etanercept therapy was well tolerated in this aged population. The therapeutic role of etanercept in patients with GCA should be evaluated in studies with a larger number of patients.

Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren’s syndrome

Abstract: Objective: To investigate the safety and efficacy of rituximab (RTX) for systemic symptoms in patients with primary Sjogren’s syndrome (pSS), and changes in B cell biomarkers. Patients and methods: The records of 16 patients with pSS according to the American European consensus group criteria were reviewed retrospectively. Results: Patients, all women, had a median age of 58.5 (range 41–71) years and a disease duration of 9.5 (range 0–25) years. RTX was prescribed for lymphoma (n = 5), refractory pulmonary disease with polysynovitis (n = 2), severe polysynovitis (n = 2), mixed cryoglobulinaemia (n = 5), thrombocytopenia (n = 1) and mononeuritis multiplex (n = 1). The median follow-up duration was 14.5 (range 2–48) months. Three patients experienced adverse events, including one mild serum sickness-like reaction with the presence of human antichimeric antibodies. Efficacy of treatment was observed in 4 of 5 patients with lymphomas and in 9 of 11 patients with systemic involvement. Dryness was improved in only a minority of patients. Corticosteroid dose was reduced in 11 patients. RTX induced decreased rheumatoid factor, γ-globulin and β2-microglobulin levels, and the level of B cell activating factor of the tumour necrosis factor family (BAFF) increased concomitantly with B cell depletion. Five patients were re-treated, with good efficacy and tolerance, except for one with probable serum sickness-like reaction. Conclusion: This study shows good efficacy and fair tolerance of RTX for systemic features. In addition, RTX allows for a marked reduction in corticosteroid use. Except for BAFF, the level of which increases, serum B cell biomarker levels decrease after taking RTX. Controlled trials should be performed to confirm the efficacy of RTX in pSS.

Minimal clinically important improvement/difference (MCII/MCID) and patient acceptable symptom state (PASS): what do these concepts mean?

Abstract: An increasing focus has over recent years been directed to the use of categorical endpoints to define response, i.e. to define cut-points for important improvement and/or acceptable clinical state. The levels of Minimal Clinically Important Improvement (MCII) are typically defined according to the patients perception of what is an important improvement. It can be defined as the smallest change in measurement that signifies an important improvement. MCII signifies an improvement of relevance in a clinical trial, or the minimal meaningful change at an individual level. The Minimal Clinically Important Difference (MCID) may reflect either an improvement or a worsening. Patient Acceptable Symptom State (PASS) has been defined as the highest level of symptom beyond which patients consider themselves well. Cut-points for MCII and PASS are usually identified through two different statistical approaches. The 75th percentage approach identifies the cut-point corresponding to the 75 percentile of the scores for improvement in patients who report an important improvement by the anchoring question. Applying receiver operating characteristic (ROC) curves allows for choosing the threshold that is the best compromise between sensitivity and specificity for each outcome criterion. The identified cut-points for MCII and PASS may easily be incorporated as endpoints in clinical trials, and will provide information about the proportion of patients that achieve an improvement exceeding the level accepted as MCII and achieve a state accepted as PASS.

Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy

Abstract: Objective: To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis. Methods: Patients completing the 6-month, double-blind period were eligible to enter the long-term extension; patients received abatacept ∼10 mg/kg, plus disease-modifying antirheumatic drugs. Safety and efficacy (American College of Rheumatology (ACR) criteria responses, DAS28 (C-reactive protein), HAQ-DI, SF-36, Medical Outcomes Study Sleep Problems Index, fatigue VAS) were assessed through 2 years. Results: 317 patients (218 from the abatacept and 99 from the placebo group) entered and 222 (70%) completed 18 months of long-term extension treatment. The incidence and type of adverse events were consistent between the double-blind and cumulative (double-blind plus long-term extension) periods. Rates of serious adverse events were 25.6 and 23.4 per 100 patient-years in the double-blind versus cumulative period. At 6 months and 2 years, using non-responder analyses, ACR responses in abatacept-treated patients were: ACR 20, 59.4% and 56.2%; ACR 50, 23.5% and 33.2%; ACR 70, 11.5% and 16.1%; HAQ-DI responses were 54.4% and 47.9%. At 6 months and 2 years, using post-hoc as-observed analyses, the percentage of patients (95% confidence interval) achieving DAS28 (C-reactive protein) low disease activity score (⩽3.2) and DAS28 (C-reactive protein)-defined remission ( Conclusion: No unique safety observations were reported during open-label exposure. Improvements in the signs and symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the 2 years in this population with difficult-to-treat disease. Trial registration number: NCT00124982.

MRI in predicting a major clinical response to anti-tumour necrosis factor treatment in ankylosing spondylitis

Abstract: Objective: To evaluate the role of MRI in predicting a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) improvement of at least 50% (BASDAI 50) upon anti-tumour necrosis factor (TNF) therapy of active ankylosing spondylitis (AS). Methods: MRIs from patients with active AS who participated in randomised controlled trials were analysed with respect to presence and extent of active inflammatory lesions as detected in the spine (n = 46), sacroiliac (SI) joints (n = 42) and both sites (n = 26). Univariate and multivariate logistic regression analyses were applied to evaluate MRI and clinical data in predicting a BASDAI 50 response. Results: The Berlin MRI spine score (odds ratio (OR) 1.16, 95% CI 1.02 to 1.33) and disease duration (OR 0.9, 95% CI 0.63 to 0.97) were statistically significant predictors of a BASDAI 50 response using regression analysis while there was only a trend for C-reactive protein (CRP). The likelihood ratio (LR) for achievement of BASDAI 50 was increased in patients with a Berlin MRI spine score ⩾11 (LR 6.7), disease duration 20 years, normal CRP and no active inflammatory lesion in the spine were highly predictive of not achieving BASDAI 50. A trend was only found for the MRI score of SI joints to be predictive. Conclusions: Widespread inflammation in the spine as detected by MRI contributes to predicting a BASDAI 50 response in active patients with AS treated with anti-TNF agents.

Are there gender differences in severity of ankylosing spondylitis? Results from the PSOAS cohort

Abstract: Objective: To examine the clinical and radiographic features in men and women in the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, a large well-defined cross-sectional study of patients with AS, in order to understand the influence of gender in determining the severity of ankylosing spondylitis. Methods: Extensive clinical assessments and spine radiographs were performed in 302 men and 100 women with AS of ⩾20 years duration. Radiographs were scored using the Bath Ankylosing Spondylitis Radiographic Index Spine (BASRI-spine) score (range 2–12). Functional impairment was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Health Assessment Questionnaire for the Spondyloarthropathies (HAQ-S). Results: Radiographic severity was worse among men. The unadjusted median BASRI-spine score for men was 10, compared with 6.5 for women (p Conclusions: Among patients with longstanding AS, men have more severe radiographic changes; findings of treatment differences suggest that women may have more peripheral arthritis. At any given level of radiographic damage, self-reported functional limitations were worse for women.

Th1 but not Th17 cells predominate in the joints of patients with rheumatoid arthritis

Abstract: Objectives: Recent animal studies have revealed critical roles of interleukin (IL)17, which is produced by a newly identified subset of helper T cells, Th17 cells, in the development of autoimmune diseases including arthritis. However, in human rheumatoid arthritis (RA), detailed characteristics and the prevalence of Th17 cells are unclear. Methods: Peripheral blood mononuclear cells (PBMC) were obtained from 123 patients with RA and 28 healthy controls. Mononuclear cells were also prepared from synovial membrane or synovial fluid of 12 patients with RA. IL17 (IL17A) positive T cells were identified by a flow cytometer after ex vivo stimulation with phorbol myristate acetate and ionomycin. Disease activity was assessed with the 28-joint Disease Activity Score (DAS28). Results: IL17 positive cells were detected in CD45RO+ CD4 T cells. Most IL17 positive T cells produced neither interferon (IFN)γ nor IL4, but tumour necrosis factor (TNF)α similar to murine Th17 cells. The frequency of Th17 cells was neither increased in RA nor correlated with DAS28. Unexpectedly, the frequency of Th17 cells was significantly decreased in the joints compared with PBMC of the same patients with RA, whereas Th1 cells were more abundant in the joints than in PBMC. Conclusions: We could not obtain evidence that positively supports predominance of Th17 cells in RA. Further careful investigation is necessary before clinical application of IL17-targeting therapy.

Progression of radiographic damage in patients with ankylosing spondylitis: defining the central role of syndesmophytes

Abstract: Background: Structural changes such as erosions, syndesmophytes and ankylosis are characteristic of ankylosing spondylitis (AS). These can be quantified by the modified Stokes Anklylosing Spondylitis Spinal Score (mSASSS). It is unknown which radiographic feature is most relevant for the assessment of change and the prediction of future damage in AS. Objectives: To analyse radiographic progression in AS by using different assessments to define the most important changes. Methods: Spinal radiographs of 116 patients with AS were scored by the mSASSS at baseline (BL) and after 2 years. Radiographic progression was assessed by differentiating (1) any change; (2) progression to syndesmophytes/ankylosis (definite change); and (3) changes exceeding the smallest detectable change (SDC) as predefined. A growth angle of 45° was used to differentiate syndesmophytes from spondylophytes. Results: Some radiographic progression after 2 years was detected in 42% of patients, novel syndesmophytes in 31% of patients, and, using the SDC (calculated at 2 mSASSS units) as cut-off, progression was seen in 28% of patients. Thus, in 74% of the patients changes were because of syndesmophytes and/or ankylosis. Using the predefined cut-off, only 12% of all syndesmophytes were spondylophytes. Patients with such changes were of older age. Definite radiographic progression was found in 44% of the patients with syndesmophytes/ankylosis at BL (n = 57) versus 19% (p = 0.03) of the patients without such changes (n = 59). Conclusions: Syndesmophytes and ankylosis are the most relevant structural changes in AS, and also in the mSASSS. Development of just one syndesmophyte within 2 years indicates progression of structural changes in AS; this is relevant for clinical practice. Syndesmophytes are the best predictors of radiographic progression.

All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists

Abstract: Background: Mortality is increased in rheumatoid arthritis (RA), mainly because of cardiovascular (CV) events, cancer and infections. Recent data suggest that treatment with tumour necrosis factor (TNF) antagonists may affect this trend. Objective: To assess whether treatment with TNF antagonists is associated with reduction in CV events, cancer and infection rates, and in mortality in patients with RA treated and not treated with TNF antagonists. Methods: BIOBADASER is a registry for active long-term follow-up of safety of biological treatments in patients with RA. It includes 4459 patients with RA treated with TNF antagonists. EMECAR is an external RA cohort (n = 789) established to define the characteristics of the disease in Spain and to assess comorbidity. The incidence density (ischaemic heart disease) of CV events, cancer and infections was estimated and compared. The standardised mortality ratio was compared with the rate in the general population. A propensity score was used to match cohorts by the probability of being treated. Results: Rates of CV and cancer events are significantly higher in EMECAR than in BIOBADASER (RR 5–7 for different CV events, and RR 2.9 for cancer), whereas the rate of serious infections is significantly higher in BIOBADASER (RR 1.6). Mortality ratio of BIOBADASER by EMECAR is 0.32 (0.20–0.53) for all causes of death, 0.58 (0.24–1.41) for CV events, 0.52 (0.21–1.29) for infection and 0.36 (0.10–1.30) for cancer-related deaths. Conclusion: Morbidity, other than infection, and mortality are not higher than expected in patients with RA treated with TNF antagonists.

Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women

Abstract: Objectives: Vitamin D has immune-modulating effects and may protect against the development of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Methods: We identified incident cases of SLE and RA among 186 389 women followed from 1980 to 2002 in the Nurses’ Health Study and Nurses’ Health Study II cohorts. We excluded subjects where SLE or RA was not confirmed by medical record review, and those who failed to return questionnaires. Semi-quantitative food frequency questionnaires assessed vitamin D intake from food and supplements. We used cumulative-updated total energy-adjusted dietary exposures for each 2-year cycle. Relationships between vitamin D intake and incident SLE and RA were examined in age-adjusted and Cox proportional hazards models, adjusted for confounders. Results were pooled using meta-analysis random effects models. Results: We confirmed 190 incident cases of SLE and 722 of RA with dietary information. Increasing levels of vitamin D intake had no relationship to the relative risk of developing either SLE or RA. Conclusions: Vitamin D intake was not associated with risk of SLE or RA in these large prospective cohorts of women.

High-resolution ultrasonography of the first metatarsal phalangeal joint in gout: a controlled study

Abstract: Objective: To compare high-resolution ultrasound (HRUS) with conventional radiography in the detection of erosions in the first metatarsophalangeal joints (1st MTPJs) of patients with gout and to identify the characteristic sonographic features of gout. Methods: HRUS examination of the 1st MTPJs of both feet was performed by two independent sonographers. The presence of joint and soft-tissue pathology was recorded. x Ray examination of the feet was performed on the same day and reported by the same radiologist. Results: 39 male patients with gout and 22 age-matched control subjects (14 with an inflammatory arthropathy and 8 disease free) were studied. The agreement on erosion between HRUS and x ray was poor, κ = 0.229 (non-weighted), with McNemar’s test being significant (p x rays. 22 MTPJs in patients with gout had never been subjected to a clinical attack of acute gout. In these MTPJs, there were 10 erosions detected by HRUS and 3 erosions on x ray. HRUS features significantly more prevalent in the patients with gout were hard and soft tophus-like lesions (p Conclusions: These data show that HRUS may assist in the management of gout in two ways: first, by aiding in the diagnosis by identifying the sonographic features that may be representative of the disease, and, second, by allowing the early detection of erosive joint damage and/or tophaceous deposits even in clinically silent joints.