Showing papers in "Rheumatology in 2011"

Irf5 promotes inflammatory macrophage polarization and th1/th17 response

Abstract: Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL-12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (TH1)-TH17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor.

Dampening inflammation by modulating tlr signalling

Abstract: Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly

Abstract: Objectives. To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages. Methods. Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients. Results. A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)]. Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)]. Conclusions. These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments.

Overview of the mucopolysaccharidoses

Abstract: The mucopolysaccharidoses (MPSs) are a group of rare, inherited lysosomal storage disorders that are clinically characterized by abnormalities in multiple organ systems and reduced life expectancy. The MPSs are heterogeneous, progressive disorders. Patients typically appear normal at birth, but during early childhood they experience the onset of clinical disease, including skeletal, joint, airway and cardiac involvement, hearing and vision impairment, and mental retardation in the severe forms of MPS I, MPS II and MPS VII and all subtypes of MPS III. There are two treatment options for patients with MPS that are directed at the underlying pathophysiology: haematopoietic stem cell transplantation, which is useful for selected patients, and recombinant i.v. enzyme replacement therapy, which is available for MPS I, II and VI. Early diagnosis and treatment can improve patient outcomes and may reduce the disease burden on patients and caregivers. As skeletal and joint abnormalities are characteristic of many patients with MPS, rheumatologists are positioned to recognize the features of the disease and to facilitate early diagnosis and referral. In this overview, the clinical features of the MPS disorders and a brief review of treatment options will be presented in order to aid the rheumatologist in recognizing the features of these rare genetic disorders.

Comparison of the epidemiology of anti-neutrophil cytoplasmic antibody-associated vasculitis between Japan and the UK

Abstract: Objectives. The epidemiological manifestations of ANCA-associated vasculitis (AAV) differ geographically. However, there have been no prospective studies comparing the incidence of AAV between Japan and Europe over the same time period using the same case definitions. Methods. The incidence of AAV was determined by a population-based method in Miyazaki prefecture, Japan, and Norfolk, UK, between 2005 and 2009. Patients with AAV were defined and classified according to the European Medicines Agency (EMEA) algorithm. Results. The number of incident cases of AAV in Japan and the UK were 86 and 50, respectively, and the average annual incidence over the 5-year period was 22.6/million (95% CI 19.1, 26.2) and 21.8/million (95% CI 12.6, 30.9) in Japan and the UK, respectively. The average age was higher in patients in Japan than in patients in the UK [mean (median), 69.7 (72) vs 60.5 (61) years]. Microscopic polyangiitis (MPA) was the predominant subtype in Japan (83%), while granulomatosis with polyangiitis (Wegener’s) was more frequent in the UK (66%). As for the pattern of ANCA positivity, >80% of Japanese patients were pANCA/ MPO positive, whereas two-thirds of UK patients were cANCA/PR3 positive. Renal involvement in MPA was very common in both countries, but was much less common in granulomatosis with polyangiitis in Japan compared with the UK. Conclusion. There was no major difference in AAV incidence between Japan and the UK, but this prospective study found MPA and MPO-ANCA to be more common in Japan and granulomatosis with polyangiitis and PR3-ANCA to be more common in the UK, in line with earlier reports.

Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis

Abstract: Objective. To analyse the clinical relevance of the production of anti-infliximab antibodies (anti-infliximab Abs) in patients with RA undergoing infliximab treatment over a prolonged period of time. Methods. Clinical characteristics, serum trough infliximab and antibody levels were evaluated in 85 RA patients treated with infliximab for a median of 4.42 (interval 0.410.2) years. DAS in 28 joints (DAS-28), EULAR response criteria and survival of treatment were assessed at 3 time points (6 months, 12 months and >4 years). Results. Antibodies against infliximab were detected in 28 (32.9%) patients and were present in all EULAR non-responder patients. Antibody levels were higher in EULAR non-responders throughout the study period (P = 0.05 at 6 months, P = 0.02 at 1 year, P = 0.003 at >4 years) compared with EULAR (good and moderate) responders. Nine (10.5%) patients, all of them with high-serum anti-infliximab Ab levels, developed infusion-related reactions. Patients with anti-infliximab Abs more often required increased infliximab doses (51.7%) (P = 0.032) and median survival time on treatment was shorter (4.15 vs 8.89 years) (P = 0.0006). MTX co-therapy was not associated with lower proportion of anti-infliximab Ab-positive patients, but those receiving both infliximab and MTX had lower levels of anti-infliximab Abs (P = 0.073) and longer survival (P = 0.015) on treatment. Conclusion. The formation of anti-infliximab Abs during treatment with infliximab is associated with a loss of clinical response, the appearance of infusion reactions and discontinuation of treatment.

Predicting arthritis outcomes—what can be learned from the Leiden Early Arthritis Clinic?

Abstract: OBJECTIVES In order to allow personalized medicine, adequate prediction of disease outcome is required. In early undifferentiated arthritis (UA), prediction of the development of RA is crucial, and in case of RA predicting the severity of the disease course may guide individualized treatment decisions. METHODS A total of 570 UA patients and 676 RA patients included in the Leiden Early Arthritis Clinic cohort were studied for baseline characteristics. The disease outcomes studied were fulfillment of the 1987 ACR-RA criteria and arthritis persistence in UA patients and the rate of radiological joint destruction and achieving sustained DMARD-free remission in RA patients. RESULTS Predictive factors for fulfillment of the 1987 ACR-RA criteria and for persistent arthritis in UA were largely similar. Risk factors for a severe rate of joint destruction were: older age (P<0.001); male gender (P<0.001); longer symptom duration at first visit (P=0.048), involvement of lower extremities (P<0.001); BMI (P<0.001); high acute phase reactants, presence of IgM-RF (P<0.001); anti-CCP2 antibodies (P<0.001); anti-modified citrullinated vimentin antibodies (P<0.001) and HLA-DRB1 shared epitope alleles (P=0.001). A high BMI was associated with a lower rate of joint destruction but with a higher risk of disease persistence. The proportion of variance in joint destruction explained was 32% CONCLUSION Predictors for RA development, previously used to develop a prediction rule in UA patients, are largely similar to predictors for arthritis persistency. Only part of the joint destruction level in RA is explained by the currently known risk factors. New factors need to be identified in order to guide pharmaceutical intervention at the level of individual RA patients.

Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials

Abstract: Objective To assess the risk of adverse events (AEs) in patients with RA treated with tocilizumab, an IL-6 receptor antibody, in published randomized controlled trials (RCTs). Methods A systematic literature search was conducted using the Cochrane library, PUBMED and EMBASE for all RCTs (of the use of tocilizumab for RA) until September 2009. Fixed effect meta-analyses were conducted to compare the incidence of AEs after treatment with tocilizumab 8 and 4 mg/kg in combination with MTX, and 8 mg/kg tocilizumab monotherapy, with controls. Pooled summary odds ratios (ORs) were calculated using the Mantel-Haenszel method. Results Six trials were analysed (four trials included 8 mg/kg tocilizumab and MTX combination therapy, three of which also assessed the 4 mg/kg dose). Three studies assessed tocilizumab monotherapy at 8 mg/kg. Pooled ORs revealed statistical significance for an increased risk of AEs in the 8 mg/kg combination group compared with controls (OR = 1.53; 95% CI 1.26, 1.86). The risk of infection was significantly higher in the 8 mg/kg combination group compared with controls (OR = 1.30; 95% CI 1.07, 1.58). No increased incidence of malignancy, tuberculosis reactivation or hepatitis was seen. Conclusion Tocilizumab in combination with MTX as a treatment for RA is associated with a small but significantly increased risk of AEs, which is comparable with that of other biologics. Vigilance for untoward effects is, therefore, imperative in any patient treated with these immuno-suppressive agents.

Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients

Abstract: SIR, Macrophage activation syndrome (MAS) belongs to the haemophagocytic lymphohistiocytic (HLH) disorders, and is one of the most feared complications of paediatric inflammatory diseases with mortality rates up to 53% [1]. Its early recognition and treatment are critical in improving outcome [2]. However, current therapeutics, including corticosteroids, ciclosporin and intravenous immunoglobulin (IVIG), do not work for all children, and the nextline treatments, such as etoposide, are associated with sepsis, a risk of secondary malignancy and up to 44% mortality rate [3]. A less immunosuppressive but effective targeted therapy is in demand. Anakinra, an IL-1 receptor antagonist, has been highly effective in treating systemic juvenile idiopathic arthritis (sJIA) [4], and MAS may occur in up to half of sJIA patients [5]. Recently, three case reports have demonstrated anakinra to effectively treat MAS as part of panniculitis, sJIA and adult onset Still’s disease [6–8]. Herein, we report the benefit of anakinra in 12 children with paediatric rheumatic disease-related MAS (prMAS). All patients at the Alberta Children’s Hospital and the Children’s Hospital of Philadelphia, who received anakinra between 2006 and 2009 for prMAS were studied retrospectively. The diagnosis of MAS was based on the combination of: (i) Ravelli’s preliminary criteria for sJIA-associated MAS [9] and (ii) HLH-2004 criteria for inherited HLH [10]. Resolution of MAS was defined by the HLH-2004 criteria [10], and included no fever, splenomegaly, cytopenia (haemoglobin 590 g/l, platelets 5100 10/l, absolute neutrophil count 5500 cells/ml) or hypertriglyceridaemia (>500 mg/l) and normalization of soluble CD25 (sCD25) if the test was performed. When prMAS occurred, all patients initially received corticosteroids (n1⁄4 12) and other immunosuppressants [IVIG (n1⁄4 9), ciclosporin (n1⁄4 10), etoposide (n1⁄4 2, one dose each) and etanercept (n1⁄4 1)] with limited benefit. Anakinra was given for better prMAS control. Etanercept and etoposide were discontinued when anakinra was initiated. In all other patients, anakinra was added to pre-existing MAS therapy at 2 mg/kg/day s.c. (maximum dose 100 mg/day) once daily. Laboratory measurements as per Ravelli’s and HLH-2004 criteria were measured before and after anakinra administration. CRP was additionally measured in selected patients. During hospitalization for prMAS, five patients were diagnosed with new-onset sJIA by the ILAR criteria, three patients with vasculitis using ACR criteria and one patient with acute rheumatic fever. Institutional Review Board approval was obtained from both institutions before the study for publication of the results of the case series. In total, 12 patients with prMAS were treated with anakinra between 2006 and 2009. Baseline characteristics are shown in Table 1. Before anakinra, five patients required intensive care, and potential infectious triggers were present in seven patients. All patients met diagnostic criteria for Ravelli’s sJIA-associated MAS [9]. Seven of 12 met the HLH-2004 criteria [10], including elevated ferritin (n1⁄4 12/12), haemophagocytosis in the bone marrow (n1⁄4 5/7), abnormal NK cell activity (n1⁄4 1/2) and elevated sCD25 (n1⁄4 4/6). The median hospitalization stay before anakinra was 11 (range 1–27) days. All patients achieved MAS remission after addition of anakinra within a median of 13 (range 2–19) days. Corticosteroids were discontinued by 6 weeks in seven patients. Of all laboratory parameters, CRP and ferritin correlated the best with MAS activity (Table 1). Median (interquartile range) CRP (n1⁄4 9/12) 2 days before the use of anakinra was 125 (95.5–183.5) mg/l compared with median 6.8 (1.9–8.9) mg/l 5 days after the use of anakinra (P1⁄4 0.0039). Patients were followed for a median of 22 (range 2–40) months, and all were in remission of MAS at the final follow-up with excellent control of the underlying rheumatic disease. There were no noted side effects from anakinra administration. We report resolution of severe prMAS following addition of anakinra to conventional immunosuppressive therapy. In these severely ill patients, anakinra was chosen over HLH-2004 treatment with etoposide and high-dose dexamethasone because of concern for sepsis, potential future malignancy and the high mortality rate associated with this protocol [3]. The clinical response was dramatic and rapid, occurring within days. All patients fully recovered, including five who had required intensive care support. In sJIA-related MAS, the mortality rate was reported in 2001 as 28% [2], yet all our patients with sJIA did well. Our three patients with vasculitis and one with rheumatic fever-associated MAS also remitted. Ravelli’s 2005 preliminary MAS criteria [9] allowed for early confirmation of MAS, although we also utilized ferritin, sCD25 and NK cell activity from the HLH-2004 criteria to confirm the diagnosis [10]. We attribute the excellent outcome in our patients to early diagnosis and immediate therapeutic intervention, including early use of anakinra. As all patients were treated with anakinra and traditional therapies, it is possible that the combination of medications contributed to the resolution of MAS. We therefore recommend anakinra in combination with high-dose corticosteroids, ciclosporin and IVIG, rather than as a sole agent. Further studies with larger patient numbers are required to better define

Prevalence of long-term oral glucocorticoid prescriptions in the UK over the past 20 years

Abstract: Objective. To assess trends in long-term (i.e. >= 3 months) oral glucocorticoid ( GC) prescriptions over the past 20 years.Methods. Data of UK adult patients registered between January 1989 and December 2008 with general practices contributing to The Health Improvement Network (THIN) database were obtained. The annual prevalence of long-term oral GC prescriptions was assessed in the whole population and specifically in people with RA, PMR/GCA, asthma, chronic obstructive pulmonary disease (COPD), Crohn's disease and ulcerative colitis (UC). Trends over the 20-year period were estimated using sex- and age-adjusted Poisson regression models.Results. During the 26 035 154 person-years of follow-up, an average of 0.75% (95% CI 0.74, 0.75) of the study population was prescribed long-term oral GC therapy at any time point. This rose from 0.59% (0.52, 0.67) in 1989 to 0.79% (0.78, 0.80) in 2008. Long-term prescriptions significantly increased in patients with RA [from 10.3% (8.7, 11.9) to 13.6% (12.9, 14.2)] and PMR/GCA [from 57.6% (53.3, 62.0) to 66.5% (65.2, 67.7)], decreased in patients with asthma, COPD and Crohn's disease and remained stable in patients with UC. However, when only incident cases were considered, we found a decreased use of GCs in patients with RA and UC [odds ratio 0.97 (95% CI 0.96, 0.97) and 0.94 (95% CI 0.93, 0.96) per increasing year, respectively].Conclusion. Over the past 20 years, long-term oral GC prescriptions have increased by 34%. Patients newly diagnosed with RA, Crohn's disease or UC are, however, less likely to receive long-term GC prescriptions than patients with a long past medical history of the disease, suggesting changes in physicians' practice.

Tumour necrosis factor antagonists and the risk of cardiovascular disease in patients with rheumatoid arthritis: a systematic literature review

Abstract: Objectives. RA is associated with early ischaemic heart disease. This appears to be driven largely by the presence of chronic inflammation. Studies suggest that treatment with disease-modifying drugs such as MTX may reduce the incidence of cardiovascular events in RA. Anti-TNF therapies significantly reduce inflammation in RA. However, the extent to which these agents also reduce cardiovascular disease (CVD) is uncertain. The purpose of this study was to explore the effect of anti-TNF agents on CVD in RA using a systematic literature review. Methods. We searched for studies of adults with RA treated with TNF antagonists where cardiovascular outcomes were recorded using MEDLINE, EMBASE, Cochrane Database, Database of Abstracts and Reviews of Effects, Health Technology Appraisal, Science Citation Index and Clinical Evidence from 1989 to 2010. Conference proceedings for the British Society of Rheumatology, ACR and EULAR between 2005 and 2009 were hand searched. Two reviewers assessed abstracts for inclusion and then quality of selected papers was assessed. Results. A total of 1840 abstracts were identified and 20 articles were suitable for inclusion. Information was obtained on the effect of TNF antagonists on overall CVD events, myocardial infarction, strokes and heart failure. Conclusion. In many studies, TNF antagonists appear to reduce the likelihood of CVD in individuals with RA. Reassuringly, there does not appear to be an increased risk of cardiac failure. However, the reduction in CVD is not as consistently seen as with studies of MTX.

Frequency and impact of symptoms experienced by patients with systemic sclerosis: results from a Canadian National Survey

Abstract: Objective. Knowledge about the range of symptoms experienced by patients with SSc, and their impact on daily functioning is limited. The objective of the present study was to identify symptoms of SSc that patients rated as frequent and that highly impacted their ability to carry out daily activities. Methods. A total of 464 persons with SSc responded to the Canadian Scleroderma Patient Survey of Health Concerns and Research Priorities, including questions regarding the frequency and impact of 69 SSc symptoms. Descriptive analyses were performed dichotomizing symptom frequencies as never or rarely vs sometimes, most of the time or always and symptom impact on daily activities as no or minimal impact vs moderate to severe impact. Results. The five highest rated symptoms in terms of frequency and moderate to severe impact on daily activities, respectively, were: fatigue (89 and 72%), RP (86 and 67%), hand stiffness (81 and 59%), joint pain (81 and 64%) and difficulty sleeping (76 and 59%). In addition to these symptoms, items related to decreased hand function (difficulty making a fist and difficulty holding objects) and pain (muscle pain and joint tenderness) were frequently endorsed and commonly associated with moderate to severe impact on daily activities. Conclusion. This study confirmed the importance for quality of life of core symptoms of SSc, such as pain, fatigue and limitations in hand function. It also identified areas with very little research, such as sleep problems, that appear to play important roles in daily functioning, and that merit more focused study.

Obesity in rheumatoid arthritis

Abstract: Obesity is a major threat for public health and its study has attracted significant attention in the general population, predominantly due to its association with significant metabolic and cardiovascular complications. In RA research, BMI is frequently reported as a demographical variable, but obesity, as such, has received little interest. This is surprising, in view of the clear associations of obesity with other arthritides, particularly OA, but also in view of the now-clear association of RA with increased cardiovascular morbidity and mortality. In this review, we summarize the studies that have looked into obesity in the RA population, evaluate their findings, identify knowledge gaps and propose directions for future research. We also pose a question of high clinical and research significance: is the use of BMI still a valid way of assessing obesity in RA?

Complex regional pain syndrome in adults

Abstract: Complex regional pain syndrome (CRPS) is a highly painful, limb-confined condition, which arises usually after trauma. It is associated with a particularly poor quality of life, and large health-care and societal costs. The causes of CRPS remain unknown. The condition’s distinct combination of abnormalities includes limb-confined inflammation and tissue hypoxia, sympathetic dysregulation, small fibre damage, serum autoantibodies, central sensitization and cortical reorganization. These features place CRPS at a crossroads of interests of several disciplines including rheumatology, pain medicine and neurology. Significant scientific and clinical advances over the past 10 years hold promise both for an improved understanding of the causes of CRPS, and for more effective treatments. This review summarizes current concepts of our understanding of CRPS in adults. Based on the results from systematic reviews, treatment approaches are discussed within the context of these concepts. The treatment of CRPS is multidisciplinary and aims to educate about the condition, sustain or restore limb function, reduce pain and provide psychological intervention. Results from recent randomized controlled trials suggest that it is possible that some patients whose condition was considered refractory in the past can now be effectively treated, but confirmatory trials are required. The review concludes with a discussion of the need for additional research.

Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case–control study

Abstract: Objective. To identify the risk factors associated with pregnancy failure in patients with APS treated with conventional therapy. Methods. A multicentre, casecontrol study was conducted to compare APS patients with successful and unsuccessful pregnancy outcomes. We retrospectively considered 410 pregnancies of women diagnosed with primary APS. The study focused on 57 unsuccessful pregnancies (considered the study population) and 57 successful pregnancies (considered the control population) matched for age and therapy. All the patients had been treated with conventional protocol treatments including low-dose aspirin and/or heparin. The clinical and laboratory features of the two groups of women diagnosed with APS were compared. Results. The independent risk factors for pregnancy failure were: (i) the presence of SLE or other autoimmune diseases [odds ratio (OR) 6.0; 95% CI 1.7, 20.8; P = 0.01]; (ii) history of both thrombosis and pregnancy morbidity (OR 12.1; 95% CI 1.3, 115.3; P = 0.03); and (iii) triple [Immunoglobulin (Ig) G/IgM aCLs plus IgG/IgM anti-b2 glycoprotein I antibodies plus LA] aPL positivity (OR 4.1; 95% CI 1.0, 16.7; P = 0.05). APS patients diagnosed on the basis of a single positive test and/or history of pregnancy morbidity alone were generally found to have successful pregnancies. Conclusion. It would seem from these findings that the risk of pregnancy failure in APS women planning to conceive can be stratified on the basis of some specific clinical and laboratory features.

Biological mechanisms of chronic fatigue

Abstract: Chronic fatigue is a common, poorly understood and disabling phenomenon in many diseases. We aim to provide an overview of fatigue in chronic autoimmune and inflammatory disease. Fatigue measurement, prevalence and confounding factors such as depression, sleep disorders and pain are reviewed in the first half of the article. In the second half of the article, we describe explanatory models of fatigue and fatigue signalling, with an emphasis on cytokines and sickness behaviour, oxidative stress, mitochondrial dysfunction and the impact of certain genes on fatigue.

High prevalence of ultrasonographic synovitis and enthesopathy in patients with psoriasis without psoriatic arthritis: a prospective case–control study

Abstract: Objective. To investigate the presence of synovitis, tenosynovitis and enthesitis with power Doppler (PD) ultrasonography (US) in patients with psoriasis without musculoskeletal diseases as compared with controls with other skin diseases without musculoskeletal disorders. Methods. A total of 162 patients with plaque psoriasis and 60 age-matched controls with other skin diseases, all without musculoskeletal diseases, were prospectively recruited at 14 centres. They underwent dermatological and rheumatological assessment and a blinded PDUS evaluation. Clinical assessment included demographics, comorbidities, severity of psoriasis, work and sport activities and musculoskeletal clinical examination. PDUS evaluation consisted of the detection of grey scale (GS) synovitis and synovial PD signal in 36 joints, GS tenosynovitis and tenosynovial PD signal at 22 sites, and GS enthesopathy and entheseal PD signal in 18 entheses. Results. US synovitis and enthesopathy were significantly more frequent in psoriatic patients than in controls (P = 0.024 and 0.005, respectively). The percentage of joints with US synovitis was 3.2% in the psoriasis group and 1.3% in the control group (P < 0.0005). US enthesopathy was present in 11.6% of entheses in the psoriasis group and 5.3% of entheses in the control group (P < 0.0005). Entheseal PD signal was found in 10 (7.4%) psoriatic patients, whereas no controls showed this finding (P = 0.05). Among demographic and clinical data, having psoriasis was the only significant predictive variable of the presence of US synovitis [odds ratio (OR) 2.1; P = 0.007] and enthesopathy (OR 2.6; P = 0.027). Conclusion. Psoriatic patients showed a significant prevalence of asymptomatic US synovitis and enthesopathy, which may indicate a subclinical musculoskeletal involvement.

What makes osteoarthritis painful? The evidence for local and central pain processing

Abstract: OA is a chronic arthritic disease characterized by pain, local tissue damage and attempts at tissue repair. Historically, cartilage damage was believed to be the hallmark of OA. However, since cartilage is an avascular, aneural tissue, the mechanisms of pain are likely to be complex and influenced by non-cartilaginous structures in the joint including the synovium, bone and soft tissue. Imaging studies reveal the presence of synovitis and bone marrow lesions that may mediate pain. The presence of local joint inflammation and altered cartilage and bone turnover in OA implicates a potential role for a range of molecular mediators in OA pain. Mechanisms of pain perception may include the activation and release of local pro-inflammatory mediators such as prostaglandins and cytokines accompanied by the destruction of tissue, which is mediated by proteases. However, clinically, there is often disparity between the degree of pain perception and the extent of joint changes in subjects with OA. Such observations have prompted work to investigate the mechanisms of central pain perception in OA. Functional MRI has identified multiple areas of the brain that are involved in OA pain processing. These data demonstrate that pain perception in OA is complex in being influenced by local factors and activation of central pain-processing pathways. In this review, we will discuss current concepts underlying the pathophysiology of pain perception in OA and suggest possible directions for the future management of pain in this condition based on recent clinical studies.

Registries in rheumatoid arthritis and autoimmune diseases: data from the French registries

Abstract: Objectives. Clinical registries have shown their effectiveness in capturing the long-term benefit of drugs in routine care. In France, two types of registry have been established to analyse the safety and efficacy of biological agents. Methods. The Research Axed on Tolerance of Biotherapies (RATIO) registry was designed to prospectively collect all cases of lymphoma and opportunistic infections occurring in patients receiving anti-TNF blockers for any indication. We also examined the results from nationwide prospective cohorts in order to investigate the safety and efficacy of rituximab (RTX), abatacept (ABA) and tocilizumab in RA and other autoimmune diseases. Results. Analysis of the RATIO registry demonstrated an increased risk of Legionella pneumophila infection in patients receiving anti-TNF therapy, a higher risk of tuberculosis [odds ratio (OR) (95% CI): 13.3 (2.6, 69.0) and 17.1 (3.6, 80.6) for infliximab and adalimumab vs etanercept, respectively], opportunistic infections and incidence of lymphoma, with mAb than with soluble-receptor anti-TNF. The characteristics of RA patients in RTX and ABA registries showed that some patients did not receive previous TNF blockers [20% in autoimmunity and RTX (AIR) and 13% in Orencia and RA (ORA)] and one-third of them were treated without concomitant DMARDs. Patients receiving RTX showed an increased proportion of severe infections (5.0/100 patient-years). Lung and cardiac comorbidities, extra-articular involvement and low immunoglobulin G before RTX were predictive factors of severe infections. In addition, the AIR registry suggested the effectiveness of RTX in patients with SLE. Conclusion. The establishment of biological registries in rheumatic diseases, in France, with their different methods, has already provided additional data to controlled trials, mainly on the risk of severe infections and lymphoma.

Treatment of severe uveitis associated with juvenile idiopathic arthritis with anti-CD20 monoclonal antibody (rituximab)

Abstract: Objective. Rituximab (RTX), a chimeric mAb directed against the B-cell marker CD20, was investigated for its anti-inflammatory effect in treating refractory uveitis associated with JIA. Methods. Case series, retrospective multicentre. JIA patients with severe uveitis with vision-threatening complications (n = 10) and with insidious onset. All patients were treated with RTX for active uveitis refractory to topical and systemic CSs, immunosuppressives and at least one of the TNF-a inhibitors. All had active arthritis. Uveitis and arthritis course were assessed before and after RTX treatment. Results. After one RTX cycle (mean follow-up 11 months, range 718 months), uveitis inactivity was achieved in seven oligoarthritis patients (ANA + , HLA-B27) for a prolonged period of time (mean 7.5 months, range 69 months). Therefore, CSs and immunosuppression could be spared. In three of four patients responding to RTX, uveitis recurred thereafter, and RTX re-treatment led to inactivity again. In another three patients (ANA + polyarthritis, n = 1; ANA + HLA-B27 + oligo- or polyarthritis, n = 2) uveitis activity persisted after RTX therapy. In seven patients, arthritis improved or was inactive after RTX treatment (PedACR30/50/70). Conclusion. RTX may represent a rescue therapy option for severe JIA-associated uveitis refractory to

The use of Systemic Lupus Erythematosus Disease Activity Index-2000 to define active disease and minimal clinically meaningful change based on data from a large cohort of systemic lupus erythematosus patients

Abstract: Objectives. To examine SLEDAI-2000 cut-off scores for definition of active SLE and to determine the sensitivity to change of SLEDAI-2000 for the assessment of SLE disease activity and minimal clinically meaningful changes in score. Methods. Data from two multi-centre studies were used in the analysis: in a cross-sectional and a longitudinal fashion. At every assessment, data were collected on SLEDAI-2000 and treatment. The cross-sectional analysis with receiver operating characteristic (ROC) curves was used to examine the appropriate SLEDAI-2000 score to define active disease and increase in therapy was the reference standard. In the longitudinal analysis, sensitivity to change of SLEDAI-2000 was assessed with multinomial logistic regression. ROC curves analysis was used to examine possible cut-points in score changes associated with change in therapy, and mean changes were estimated. Results. In the cross-sectional analysis, the most appropriate cut-off scores for active disease were 3 or 4. In the longitudinal analysis, the best model for predicting treatment increase was with the change in SLEDAI-2000 score and the score from the previous visit as continuous variables. The use of cut-points was less predictive of treatment change than the use of continuous score. The mean difference in the change in SLEDAI-2000 scores, adjusted for prior score, between patients with treatment increase and those without was 2.64 (95% CI 2.16, 3.14). Conclusions. An appropriate SLEDAI-2000 score to define active disease is 3 or 4. SLEDAI-2000 index is sensitive to change. The use of SLEDAI-2000 as a continuous outcome is recommended for comparative purposes.

Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen-activated protein kinases and nuclear factor-κB in human osteoarthritis chondrocytes

Abstract: Objective. To investigate whether advanced glycation end products (AGEs) induce the expression of IL-6 and IL-8 through the receptor for AGEs (RAGE)-activated pathways in human OA chondrocytes. Methods. OA chondrocytes were stimulated with AGE-modified BSA (AGE-BSA). Gene expression of IL-6 and IL-8 was quantified by TaqMan assays and the production was determined using ELISAs. Immunoblotting was used to analyse the activation of mitogen-activated protein kinases (MAPKs) and the degradation of IκBα. Activation of NF-κB was determined using an ELISA. Pharmacological studies to elucidate the involved pathways were executed using transfection with small interfering RNAs (siRNAs), inhibitors of MAPKs and NF-κB. Results. AGE-BSA induced the expression of IL-6 and IL-8 in OA chondrocytes, which was inhibited by pre-treatment with soluble RAGE (sRAGE) or RAGE knockdown by siRNAs. Treatment with SB202190 (p38-MAPK inhibitor) or PD98059 (ERK inhibitor) inhibited AGE-BSA-induced IL-6 and IL-8 expression. However, SP600125 (JNK inhibitor) had no effect on AGE-BSA-induced IL-6 expression but inhibited the expression of IL-8. Treatment with NF-κB inhibitors suppressed AGE-BSA-induced IL-6 and IL-8 expression. Conclusions. This is the first study to demonstrate that AGEs induce the expression of IL-6 and IL-8 in OA chondrocytes. A novel finding of our studies is that in OA chondrocytes, AGE-BSA-induced expression of IL-6, but not of IL-8, was independent of the JNK pathway. Activation of NF-κB was an absolute requirement for both IL-6 and IL-8 expression. These results demonstrate that AGE-BSA-induced expression of IL-6 and IL-8 via RAGE is mediated through different MAPK signalling pathways in OA and possibly in other degenerative diseases.

Therapy for the mucopolysaccharidoses

Abstract: Better understanding of disease pathophysiology, improved supportive care and availability of diseasespecific treatments for some of the mucopolysaccharidosis (MPS) disorders have greatly improved the outlook for patients with MPS disorders. Optimal management of these multisystemic disorders involves a multidisciplinary team and regular, comprehensive follow-up. Enzyme replacement therapy (ERT) is now available for MPS I (Hurler, HurlerScheie and Scheie syndromes) (laronidase), MPS II (Hunter syndrome) (idursulfase) and MPS VI MaroteauxLamy (galsulfase), and is in development for MPS IV (Morquio syndrome) and MPS VII (Sly syndrome). Benefits of ERT can include improved walking ability, improved respiration and enhanced quality of life. Haematopoietic stem cell transplantation (HSCT) can preserve cognition and prolong survival in very young children with the most severe form of MPS I, and is under investigation for several other MPS disorders. Better tissue matching techniques, improved graft-vs-host prophylaxis and more targeted conditioning regimens have improved morbidity and mortality associated with HSCT.

Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review

Abstract: Objectives. To critically evaluate the evidence regarding complementary and alternative medicine (CAM) taken orally or applied topically (excluding glucosamine and chondroitin) in the treatment of OA. Methods. Randomized clinical trials of OA using CAMs, in comparison with other treatments or placebo, published in English up to January 2009, were eligible for inclusion. They were identified using systematic searches of bibliographic databases and manual searching of reference lists. Information was extracted on outcomes, and statistical significance, in comparison with alternative treatment of placebo, and side effects were reported. The methodological quality of the primary studies was determined. Results. The present review found consistent evidence that capsaicin gel and S-adenosyl methionine were effective in the management of OA. There was also some consistency to the evidence that Indian Frankincense, methylsulphonylmethane and rose hip may be effective. For other substances with promising evidence, the evidence base was either insufficiently large or the evidence base was inconsistent. Most of the CAM compounds studied were free of major adverse effects. Conclusion. The major limitation in reviewing the evidence is the paucity of randomized controlled trials in the area: widening the evidence base, particularly for those compounds for which there is promising evidence, should be a priority for both researchers and funders.

Abatacept treatment for rheumatoid arthritis

Abstract: Significant advances in our understanding of RA and its management have been made in the past decade, resulting in earlier intervention with biologic DMARDs, particularly in patients with evidence of aggressive, erosive disease. Here, one such biologic therapy, the T-cell co-stimulation modulator abatacept, is discussed, exploring clinical evidence published to date on its use in patients with very early arthritis/early RA who are MTX naive, and in patients with established RA and an inadequate response to MTX or TNF antagonists. Data from relevant clinical trials are overviewed, discussing the clinical efficacy of abatacept in early disease, the clinical outcomes over long-term treatment in different patient populations and the effects of abatacept on structural damage. Findings from integrated safety analyses of abatacept clinical trial data, representing 10 366 patient-years of exposure are described, and clinically important safety events, including serious infections, malignancies and autoimmune events, are highlighted. It is concluded that abatacept represents an effective treatment option with an established safety profile across different patient populations, including patients with both early and erosive RA and those with established disease. Furthermore, efficacy data from studies in patients with early disease suggest that the risk–benefit profile of abatacept may be more favourable when introduced earlier in the treatment paradigm.

Effectiveness of community- and workplace-based interventions to manage musculoskeletal-related sickness absence and job loss: a systematic review

Abstract: This systematic review assesses the effectiveness of interventions in community and workplace settings to reduce sickness absence and job loss in workers with musculoskeletal disorders (MSDs). Relevant studies (randomised controlled trials (RCTs) and cohort studies published since 1990) were identified by screening citations in 35 earlier systematic reviews and from searches of Medline and Embase to April 2010. Among 42 studies (54 reports) including 34 RCTs, 27 assessed return to work, 21 duration of sickness absence, and five job loss. Interventions included exercise therapy, behavioural change techniques, workplace adaptations and provision of additional services. Studies were typically small (median sample size 107 (inter-quartile range (IQR) 77 to 148) and limited in quality. Most interventions were reported as beneficial: the median relative risk (RR) for return to work was 1.21 (IQR 1.00 – 1.60) and that for avoiding MSD-related job loss, 1.25 (IQR 1.06-1.71); the median reduction in sickness absence was 1.11 (IQR 0.32 to 3.20) days/month. However, effects were smaller in the larger and better quality studies, suggesting publication bias. No intervention was clearly superior to others, although effort-intensive interventions were less effective than simple ones. No cost-benefit analyses established statistically significant net economic benefits. Given that benefits are small and of doubtful cost-effectiveness, employers’ practice should be guided by their value judgements about the uncertainties. Expensive interventions should be implemented only with rigorous cost-benefit evaluation planned from the outset. Future research should focus on the cost-effectiveness of simple low cost interventions, and further explore impacts on job retention.

Vascular function and morphology in rheumatoid arthritis: a systematic review

Abstract: OBJECTIVES: RA associates with significantly increased morbidity and mortality from cardiovascular disease (CVD). This may be due to complex interactions between traditional CVD risk factors, systemic rheumatoid inflammation and the vasculature. We reviewed the current literature to answer: (i) whether there is sufficient evidence that patients with RA have altered vascular function and morphology compared with normal controls; (ii) whether there is sufficient evidence to determine if such changes relate predominantly to systemic inflammation; and (iii) whether any changes of vascular function and morphology in RA can be modified with therapy. METHODS: The MEDLINE database was searched to identify publications from 1974 to 1 November 2010 pertaining to vascular function and morphology in RA. The total number of articles included in the present review was 93. This included 57 cross-sectional studies, 27 longitudinal studies without randomization and 9 longitudinal studies with randomization. RESULTS: Vascular function and morphology was impaired in RA relative to healthy controls. The majority of studies reported no associations between systemic inflammation and vascular function. Treatment with anti-inflammatory medication resulted in both transient and long-term improvements in the vasculature, but only a few studies reported associations between change in inflammation and change in vascular function and morphology. CONCLUSION: The link between systemic inflammation and vascular function and morphology is not wholly supported by the available literature. Long-term studies examining specific predictors (including CVD risk factors) on the vasculature in RA are needed.

Safety of anti-tumour necrosis factor agents in patients with chronic hepatitis C infection: a systematic review

Abstract: Objectives To identify all of the patients affected by chronic hepatitis C infection treated with TNF-α blockers (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab) in order to evaluate the safety profile. Methods A systematic review of the literature from January 1990 to October 2010. Results In total, 37 publications with data on 153 patients who were treated with anti-TNF-α agents in the setting of HCV infection were found. The mean anti-TNF-α treatment duration was 11.9 months. Ninety-one patients had RA, 22 had psoriasis, 6 had Crohn's disease and 14 patients had other chronic inflammatory diseases. To date, etanercept is the biological agent that has been most extensively used in the patients with HCV infection, with only one definitely confirmed case of HCV hepatitis worsening and five suspected cases (elevation of transaminases not associated with an increase in the HCV viral load and vice versa) in 110 treated patients. Treatment with this agent resulted in stable levels of liver transaminases and a stable viral load in 74 patients, with an improvement in HCV chronic liver disease in combination with IFN-ribavirin therapy in 29 patients. Conclusions The safety profile of anti-TNF-α agents in the setting of HCV infection seems to be acceptable, even if differences in the hepatotoxic profile are apparent between different agents. In the absence of long-term and large, controlled clinical trials a definitive statement on the safety of anti-TNF-α therapies in the setting of chronic HCV infection cannot be made.

Assessment of a lupus nephritis cohort over a 30-year period

Abstract: Objective. LN is a common and potentially severe complication of SLE. Our aim was to characterize a LN cohort followed at a single centre for 30 years and assess its evolution over time. Methods. Between 1975 and 2005, 156 LN patients were followed up at University College Hospital London. We divided them into three groups depending on the date of recognition of renal involvement (197585, 198695 and 19962005) and compared them in terms of clinical, demographic and serological characteristics and disease outcome. Results. Clinical characteristics were comparable between groups; however, the proportion of Afrocaribbean (AC) patients and the prevalence of anti-ENA antibodies rose significantly over time. The 5-year mortality rate decreased by 60% between the first and second decades, remaining stable over the third decade. The 5-year end-stage renal disease (ESRD) rate remained constant. An increasing number of renal transplants (RTx) was performed with encouraging results. AC origin was associated with a poorer overall prognosis. Conclusion. LN, a common complication of SLE, is associated with increased mortality and morbidity, particularly among AC patients. Despite encouraging results for RTx, once ESRD is established the prognosis is relatively poor and no improvement in preventing its development was achieved. Moreover, although a significant decrease in mortality was observed, it has remained stable for 10 years. These results suggest that we have maximized the benefits of conventional therapies and if further improvement is to be achieved, novel drug regimens must be developed.