Showing papers in "Annals of the Rheumatic Diseases in 2010"
Medical University of Vienna1, Boston University2, Arthritis Research UK3, Johns Hopkins University4, University of California, San Francisco5, Charité6, University of Toronto7, National Jewish Health8, Harvard University9, University of Paris10, University of Leeds11, Catholic University of the Sacred Heart12, Erasmus University Rotterdam13, University of Colorado Denver14, Leiden University15, University of California, San Diego16, University of Massachusetts Medical School17, University of Michigan18, University of Washington19, McGill University20, University of Pittsburgh21, Ministry of Health (New Zealand)22, New York University23, University of Manchester24, University of Amsterdam25
TL;DR: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features.
Abstract: Objective The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. Methods A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’. Results In the new criteria set, classification as ‘definite RA’ is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acute-phase response (range 0–1) and symptom duration (two levels; range 0–1). Conclusion This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct ‘RA’.
5,964 citations
Utrecht University1, Leiden University2, University of Crete3, Humboldt University of Berlin4, University of Genoa5, University of Paris6, University of Leeds7, Hospital for Special Surgery8, University of Santiago de Compostela9, University of Erlangen-Nuremberg10, University of Toronto11, University of Glasgow12, Autonomous University of Madrid13
TL;DR: The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.
Abstract: Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA).
1,676 citations
Medical University of Vienna1, Maastricht University2, Leiden University3, Paris Descartes University4, University of Leeds5, Pierre-and-Marie-Curie University6, Utrecht University7, Humboldt State University8, University of Montpellier9, University of Genoa10, University of Santiago, Chile11, Autonomous University of Madrid12, University of Glasgow13, Charles University in Prague14, Radboud University Nijmegen15, King's College London16, Sapienza University of Rome17, Karolinska Institutet18, Oregon Health & Science University19, Tufts University20, Charité21
TL;DR: In this article, the authors present a set of recommendations for the treatment of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects.
Abstract: Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-a-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.
1,372 citations
TL;DR: Ten recommendations were made for CV risk management in patients with rheumatoid arthritis, and the strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.
Abstract: Objectives: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Methods: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR’s ‘‘standardised operating procedures’’, the multidisciplinary steering committee formulated evidencebased and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. Results: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk. Conclusions: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.
1,240 citations
Hacettepe University1, Istituto Giannina Gaslini2, Aarhus University3, Rambam Health Care Campus4, Istanbul University5, Catholic University of the Sacred Heart6, University of São Paulo7, Sheba Medical Center8, Seconda Università degli Studi di Napoli9, University of Latvia10, Rio de Janeiro State University11, University of Zagreb12, University of Chieti-Pescara13, Alfaisal University14, Saint Petersburg State Pediatric Medical University15, Charité16, Children's Memorial Hospital17, Autonomous University of Madrid18, University of Tartu19, Innsbruck Medical University20, Tbilisi State Medical University21, University of Genoa22
TL;DR: The previously proposed classification criteria for Henoch–Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (C-WG) and c-Takayasu arteritis ( c-TA) are validated.
Abstract: Objectives To validate the previously proposed classification criteria for Henoch–Schonlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). Methods Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis ≤18 years. Step 2: blinded classification by consensus panel of a representative sample of 280 cases. Step 3: statistical (sensitivity, specificity, area under the curve and κ-agreement) and nominal group technique consensus evaluations. Results 827 patients with HSP, 150 with c-PAN, 60 with c-WG, 87 with c-TA and 52 with c-other were compared with each other. A patient was classified as HSP in the presence of purpura or petechiae (mandatory) with lower limb predominance plus one of four criteria: (1) abdominal pain; (2) histopathology (IgA); (3) arthritis or arthralgia; (4) renal involvement. Classification of c-PAN required a systemic inflammatory disease with evidence of necrotising vasculitis OR angiographic abnormalities of medium-/small-sized arteries (mandatory criterion) plus one of five criteria: (1) skin involvement; (2) myalgia/muscle tenderness; (3) hypertension; (4) peripheral neuropathy; (5) renal involvement. Classification of c-WG required three of six criteria: (1) histopathological evidence of granulomatous inflammation; (2) upper airway involvement; (3) laryngo-tracheo-bronchial involvement; (4) pulmonary involvement (x-ray/CT); (5) antineutrophilic cytoplasmic antibody positivity; (6) renal involvement. Classification of c-TA required typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of five criteria: (1) pulse deficit or claudication; (2) blood pressure discrepancy in any limb; (3) bruits; (4) hypertension; (5) elevated acute phase reactant. Conclusion European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society propose validated classification criteria for HSP, c-PAN, c-WG and c-TA with high sensitivity/specificity.
1,063 citations
University of Basel1, Radboud University Nijmegen2, University of Padua3, Complutense University of Madrid4, University of Paris5, University of Zurich6, University of Bari7, Lithuanian University of Health Sciences8, University of Florence9, Russian Academy10, Rambam Health Care Campus11, University of Regensburg12, Charité13, University of the Witwatersrand14, Johns Hopkins University15, University of Coimbra16, University of Verona17, Lund University18, University of Ljubljana19, Utrecht University20, University of Pécs21, Medical University of Vienna22, University of Debrecen23, Sapienza University of Rome24, University of Geneva25, University of Silesia in Katowice26, University College London27, University of Tübingen28, Military Medical Academy29, Lille University of Science and Technology30, University of Michigan31, Iuliu Hațieganu University of Medicine and Pharmacy32, Charles University in Prague33, University of Zagreb34
TL;DR: Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.
Abstract: Objectives To determine the causes and predictors of mortality in systemic sclerosis (SSc). Methods Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. Results Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). Conclusion Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.
1,010 citations
TL;DR: High levels of evidence were found that AMs prevent lupus flares and increase long-term survival of patients with SLE; moderate evidence of protection against irreversible organ damage, thrombosis and bone mass loss and evidence supporting an effect on severe l upus activity, lipid levels and subclinical atherosclerosis was weak.
Abstract: Background: Antimalarial drugs (AM), chloroquine (CQ) and hydroxychloroquine (HCQ), are frequently withdrawn in lupus patients with either severe or remitting disease. However, additional effects beyond immunomodulation have been recently described. Our aim was to analyse all the published evidence of the beneficial and adverse effects of AM therapy in SLE. Methods: Systematic review of the English literature between 1982-2007 using MEDLINE and EMBASE. Randomised controlled trials (RCTs) and observational studies were selected. Case reports were excluded except for toxicity reports. The GRADE system was used to analyse the quality of the evidence. Results: 95 articles were included in the systematic review. We have found high evidence that AM prevent lupus flares and increase long-term survival of SLE patients; moderate evidence of protection against irreversible organ damage, thrombosis and bone mass loss .Toxicity related to AM is infrequent, mild and usually reversible, with HCQ having a safer profile. In pregnant women, we have found high evidence that AM, particularly HCQ, decrease lupus activity without harming the baby. On the other hand, evidence supporting an effect on severe lupus activity, lipid levels and subclinical atherosclerosis was weak. Individual papers suggest effects in preventing the evolution from SLE-like to full-blown SLE, influencing vitamin D levels and protecting lupus patients against cancer. Conclusion: Given the broad spectrum of beneficial effects and the safety profile, HCQ should be given to most patients with SLE during the whole course of the disease, irrespective of its severity, and be continued during pregnancy.
815 citations
TL;DR: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit–risk, in patients for whom treatment with methotRexate or biological agents has not previously failed.
Abstract: Background: The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. Objective: To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed. Methods: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24. Results: The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p 3×– Conclusion: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit–risk, in patients for whom treatment with methotrexate or biological agents has not previously failed. Trial registration number: NCT00109408
728 citations
TL;DR: The ESSDAI is a clinical index designed to measure disease activity in patients with primary Sjögren's syndrome and should facilitate clinical research and be helpful as an outcome measure in clinical trials.
Abstract: Objective To develop a disease activity index for patients with primary Sjogren9s syndrome (SS): the European League Against Rheumatism (EULAR) Sjogren9s syndrome disease activity index (ESSDAI). Methods Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific ‘domains’ contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0–10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain. Results All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p Conclusions The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials.
706 citations
TL;DR: The rate of TB in patients with RA treated with anti-TNF therapy was three- to fourfold higher in patients receiving INF and ADA than in those receiving ETA.
Abstract: Background The risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) is thought to be increased following anti-tumour necrosis factor (anti-TNF) therapy, with a proposed differential risk between the anti-TNF drugs etanercept (ETA), infliximab (INF) and adalimumab (ADA). Objective To compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity. Methods Data from the British Society for Rheumatology Biologics Register (BSRBR), a national prospective observational study, were used to compare TB rates in 10 712 anti-TNF treated patients (3913 ETA, 3295 INF, 3504 ADA) and 3232 patients with active RA treated with traditional disease-modifying antirheumatic drugs. Results To April 2008, 40 cases of TB were reported, all in the anti-TNF cohort. The rate of TB was higher for the monoclonal antibodies ADA (144 events/100 000 person-years) and INF (136/100 000 person-years) than for ETA (39/100 000 person-years). After adjustment, the incidence rate ratio compared with ETA-treated patients was 3.1 (95% CI 1.0 to 9.5) for INF and 4.2 (1.4 to 12.4) for ADA. The median time to event was lowest for INF (5.5 months) compared with ETA (13.4 months) and ADA (18.5 months). 13/40 cases occurred after stopping treatment. 25/40 (62%) cases were extrapulmonary, of which 11 were disseminated. Patients of non-white ethnicity had a sixfold increased risk of TB compared with white patients treated with anti-TNF therapy. Conclusion The rate of TB in patients with RA treated with anti-TNF therapy was three- to fourfold higher in patients receiving INF and ADA than in those receiving ETA.
637 citations
University of Crete1, University of Ioannina2, Dresden University of Technology3, Leiden University4, University of Pisa5, University of Manchester6, Imperial College London7, University of Padua8, Dalhousie University9, University College London10, Pierre-and-Marie-Curie University11, University of Düsseldorf12, Medical University of Vienna13, National and Kapodistrian University of Athens14, Karolinska Institutet15, National Institutes of Health16, University of Birmingham17
TL;DR: Neuropsychiatric manifestations in SLE patients should be first evaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.
Abstract: Objectives To develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations. Methods The authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design. Results Systemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence >5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1–5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fi vefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fl uid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fl uid-attenuating inversion recovery, diffusion-weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to refl ect an infl ammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD. Conclusions Neuropsychiatric manifestations in SLE patients should be fievaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.
TL;DR: Whether smoking is a risk factor for developing rheumatoid arthritis (RA) is assessed, especially RF+ RA men and heavy smokers.
Abstract: Objectives: To assess whether smoking is a risk factor for developing rheumatoid arthritis (RA). Design: Meta-analysis. Method: Data sources were observational studies that examined the association between smoking history and the risk of developing RA identified through Medline and EMBASE (from 1966 to December 2006), relevant books and a reference search. Two authors independently extracted the following: authors’ names, publication year, sample size, participant characteristics, odds ratios (OR) or relative risks, adjustment factors, study design and area where the study was conducted. Data syntheses were based upon random effects model. Summarised syntheses effects were expressed by OR. Results: Sixteen studies were selected from among 433 articles. For men, summary OR for ever, current and past smokers were 1.89 (95% CI 1.56 to 2.28), 1.87 (1.49 to 2.34) and 1.76 (1.33 to 2.31), respectively. For rheumatoid factor-positive (RF+) RA, summary OR for ever, current and past smokers were 3.02 (2.35 to 3.88), 3.91 (2.78 to 5.50) and 2.46 (1.74 to 3.47), respectively. Summary OR for 20 or more pack-years of smoking was 2.31 (1.55 to 3.41). For women, summary OR for ever, current and past smokers were 1.27 (1.12 to 1.44), 1.31 (1.12 to 1.54) and 1.22 (1.06 to 1.40), respectively. For RF+ RA, summary OR for ever, current and past smokers were 1.34 (0.99 to 1.80), 1.29 (0.94 to 1.77) and 1.21 (0.83 to 1.77). Summary OR for 20 or more pack-years of smoking was 1.75 (1.52 to 2.02). Conclusion: Smoking is a risk factor for RA, especially RF+ RA men and heavy smokers.
TL;DR: 10 key recommendations for diagnosis of knee OA were developed using both research evidence and expert consensus and although there is no agreed reference standard, thorough clinical assessment alone can provide a confident rule-in diagnosis.
Abstract: Objective To develop evidence-based recommendations for the diagnosis of knee osteoarthritis (OA). Methods The multidisciplinary guideline development group, representing 12 European countries, generated 10 key propositions regarding diagnosis using a Delphi consensus approach. For each recommendation, research evidence was searched systematically. Whenever possible, the sensitivity, specificity and likelihood ratio were calculated for individual diagnostic indicators and a diagnostic ladder was developed using Bayes' method. Secondary analyses were undertaken to test directly the recommendations using multiple predictive models in two populations from the UK and the Netherlands. Strength of recommendation was assessed by the EULAR visual analogue scale. Results Recommendations covered the definition of knee OA and its risk factors, subsets, typical symptoms and signs, the use of imaging and laboratory tests and differential diagnosis. Three symptoms (persistent knee pain, limited morning stiffness and reduced function) and three signs (crepitus, restricted movement and bony enlargement) appeared to be the most useful. Assuming a 12.5% background prevalence of knee OA in adults aged >= 45 years, the estimated probability of having radiographic knee OA increased with increasing number of positive features, to 99% when all six symptoms and signs were present. The performance of the recommendations in the study populations varied according to the definition of knee OA, background risk and number of tests applied. Conclusion 10 key recommendations for diagnosis of knee OA were developed using both research evidence and expert consensus. Although there is no agreed reference standard, thorough clinical assessment alone can provide a confident rule-in diagnosis.
TL;DR: This study provides the first definition of a “state” of MDA in PsA and defines a target for treatment, which must now be validated in other populations and tested in clinical trials.
Abstract: Objective: To create minimal disease activity (MDA) criteria for psoriatic arthritis (PsA). With recent therapeutic advances, this is now a goal for treatment and may represent a measure to compare therapies. It defines a satisfactory state of disease activity rather than a change, and encompasses all aspects of the disease. Methods: 40 patient profiles were sampled from an observational PsA database. Sixty experts in PsA classified these as in MDA or not. A consensus of ⩾70% was accepted, identifying 13 profiles in MDA. Summary statistics created possible cut-off points for the definition. Considering the number of measures that must be met, 35 candidate definitions were created and tested using receiver operating characteristic curves (ROC) for sensitivity and specificity. Results: Four candidate definitions showed high area under the curve values on ROC testing. Definitions with high outlying values were excluded as they were not considered to represent MDA. Aiming for high specificity to reduce false positives resulted in a preference for the following definition: “A patient is classified as achieving MDA when meeting 5 of the 7 following criteria: tender joint count ⩽1; swollen joint count ⩽1; Psoriasis Activity and Severity Index ⩽1 or body surface area ⩽3; patient pain visual analogue score (VAS) ⩽15; patient global disease activity VAS ⩽20; health assessment questionnaire ⩽0.5; tender entheseal points ⩽1”. Conclusion: This study provides the first definition of a “state” of MDA in PsA and defines a target for treatment. It must now be validated in other populations and tested in clinical trials.
TL;DR: The data confirm that a LD IVCY regimen followed by AZA—the “Euro-Lupus regimen”—achieves good clinical results in the very long term.
Abstract: OBJECTIVE: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomized prospective trial comparing low-dose (LD) versus high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. PATIENTS AND METHODS: Data regarding survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomized in the ELNT, except in 6 lost to follow-up. RESULTS: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (11% vs 4%, 14% vs 11% and 5% vs 9%, respectively) nor did mean serum creatinine, 24-h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressants and blood pressure lowering drugs. We confirm, after 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy. CONCLUSION: Our data confirm that a LD IVCY regimen followed by AZA - the "Euro-Lupus regimen" - achieves good clinical results in the very long-term.
TL;DR: Recommendations have been suggested that represent a realistic first step in the standardisation of diagnostic tests for autoimmune diseases and help to reduce the cost of repeated confirmatory tests.
Abstract: The impact of autoimmune diseases is growing from both a clinical and a laboratory point of view. Diagnostic assays are now being transferred from dedicated specialised laboratories into high-throughput service laboratories. The increasing number of available methods has raised the variability among the laboratories, making their reproducibility a critical problem. On the other hand, reliable tests are needed for early diagnosis and prompt treatment, and the cost of repeated confirmatory tests should be reduced and unnecessary further investigations avoided. New methodologies, particularly for antinuclear antibodies (ANAs), have been applied to autoantibody detection in order to screen and process larger volumes of clinical specimens more quickly and at less cost than the traditional methods. However, because of the lack of their sensitivity to detect all ANAs and standardisation, inaccuracies (including false positives and negatives) in the results have been reported. A committee of the American College of Rheumatology was formed to address this issue. Specific recommendations have been suggested that represent a realistic first step in the standardisation of diagnostic tests for autoimmune diseases.
TL;DR: Fewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance and over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups.
Abstract: Long-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment.
TL;DR: There is good evidence for the efficacy of biological agents in patients with RA and safety data confirm an increased risk of bacterial infection and TB with TNFi compared with conventional DMARDs.
Abstract: Objectives To review the evidence for the efficacy and safety of biological agents in patients with rheumatoid arthritis (RA) to provide data to develop treatment recommendations by the European League Against Rheumatism (EULAR) Task Force. Methods Medline, Embase and Cochrane databases were searched for relevant articles on infliximab (IFX), etanercept (ETN), adalimumab (ADA), certolizumab-pegol (CZP), golimumab (GLM), anakinra (ANA), abatacept (ABT), rituximab (RTX) and tocilizumab (TCZ) published between 1962 and February 2009; published abstracts from the 2007–2008 American College of Rheumatology (ACR) and EULAR conference were obtained. Results 87 articles and 40 abstracts were identified. In methotrexate (MTX) naive patients, biological therapy with IFX, ETN, ADA, GLM or ABT has been shown to improve clinical outcomes (level of evidence 1B). In MTX/other synthetic disease-modifying antirheumatic drug (DMARD) failures all nine biological agents confer benefit (1B), with lower efficacy noted for ANA. RTX, ABT, TCZ and GLM demonstrate efficacy in tumour necrosis factor inhibitor (TNFi) failures (1B). Less evidence exists for switching between IFX, ETN and ADA (3B). Biological and MTX combination therapy is more efficacious than a biological agent alone (1B). A safety review shows no increased malignancy risk compared with conventional DMARDs (3B). TNFi are generally associated with an increased risk of serious bacterial infection, particularly within the first 6 months of treatment initiation; increased tuberculosis (TB) rates with TNFi are highest with the monoclonal antibodies (3B). Conclusions There is good evidence for the efficacy of biological agents in patients with RA. Safety data confirm an increased risk of bacterial infection and TB with TNFi compared with conventional DMARDs.
TL;DR: The evidence that targeting low-disease activity or remission in the management of RA conveys better outcomes than routine care is expanded, allowing concluding that a target-oriented approach leads to less comorbidities and cardiovascular risk and better work productivity than conventional care.
Abstract: Objective A systematic literature review (SLR; 2009–2014) to compare a target-oriented approach with routine management in the treatment of rheumatoid arthritis (RA) to allow an update of the treat-to-target recommendations.
Methods Two SLRs focused on clinical trials employing a treatment approach targeting a specific clinical outcome were performed. In addition to testing clinical, functional and/or structural changes as endpoints, comorbidities, cardiovascular risk, work productivity and education as well as patient self-assessment were investigated. The searches covered MEDLINE, EMBASE, Cochrane databases and Clinicaltrial.gov for the period between 2009 and 2012 and separately for the period of 2012 to May of 2014.
Results Of 8442 citations retrieved in the two SLRs, 176 articles underwent full-text review. According to predefined inclusion/exclusion criteria, six articles were included of which five showed superiority of a targeted treatment approach aiming at least at low-disease activity versus routine care; in addition, publications providing supportive evidence were also incorporated that aside from expanding the evidence provided by the above six publications allowed concluding that a target-oriented approach leads to less comorbidities and cardiovascular risk and better work productivity than conventional care.
Conclusions The current study expands the evidence that targeting low-disease activity or remission in the management of RA conveys better outcomes than routine care.
TL;DR: In this paper, the authors investigated the effects of mesenchymal stem cells on collagen-reactive RA human T-cell proliferation and cytokine production, as well as on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes.
Abstract: Objectives: Adult mesenchymal stem cells were recently found to suppress effector T-cell and inflammatory responses and have emerged as attractive therapeutic candidates for immune disorders. In rheumatoid arthritis (RA), a loss in the immunological self-tolerance causes the activation of autorreactive T cells against joint components and subsequent chronic inflammation. The aim of this study is to characterize the immunosuppresive activity of human adipose-derived mesenchymal stem cells (hASCs) on collagen-reactive T cells from RA patients. Methods: We investigated the effects of hASCs on collagen-reactive RA human T-cell proliferation and cytokine production, as well as on the production of inflammatory mediators by monocytes and fibroblast-like synoviocytes from RA patients. Results: hASCs suppressed antigen-specific response of T cells from RA patients. hASCs inhibited the proliferative response and the production of inflammatory cytokines by collagen-activated CD4 and CD8 T cells. In contrast, the number of IL-10-producing T cells and monocytes significantly augmented upon hASC-treatment. The suppressive activity of hASCs was both cell-to-cell contact-dependent and -independent. hASCs also stimulated the generation of FoxP3-expressing CD4+CD25+ regulatory T cells with capacity to suppress collagen-specific T-cell responses. Finally, hASCs donwregulated the inflammatory response and the production of matrix-degrading enzymes by synovial cells isolated from RA patients. Conclusions: Our work identifies to hASCs as key regulators of immune tolerance with capacity to suppress T-cell and inflammatory responses to induce the generation/activation of antigen-specific regulatory T cells.
TL;DR: Allogeneic MSCT in patients with refractory lupus resulted in amelioration of disease activity, improvement in serological markers and stabilisation of renal function, and MSCT appears beneficial in treatment of patients with SLE refracted to conventional treatment options.
Abstract: Objective To determine the safety and efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in refractory systemic lupus erythematosus (SLE). Methods A total of 15 patients with persistently active SLE underwent MSCT. Outcome was evaluated by changes in the SLE disease activity index (SLEDAI), serological features (anti-nuclear antibodies and anti-double-stranded DNA (anti-dsDNA)), renal function and percentage of peripheral blood regulatory T cells. Results From 11 March 2007 to 4 November 2008, 15 patients with persistently active SLE were enrolled and underwent MSCT. The mean follow-up period was 17.2±9.5 months. A total of 13 patients have been followed for more than 12 months. All patients clinically improved following treatment with mesenchymal stem cells with a marked decrease in the SLEDAI score and 24 h proteinuria. At 12-month follow-up, SLEDAI scores decreased from 12.2±3.3 to 3.2±2.8 and proteinuria decreased from 2505.0±1323.9 to 858.0±800.7 mg/24 h (all p Conclusion Allogeneic MSCT in patients with refractory lupus resulted in amelioration of disease activity, improvement in serological markers and stabilisation of renal function. MSCT appears beneficial in treatment of patients with SLE refractory to conventional treatment options.
TL;DR: In knees with osteoarthritis, varus and valgus alignment each increased the risk of progression in the biomechanically stressed compartment, and Varus but not valGus alignment increased therisk of incident tibiofemoral osteOarthritis.
Abstract: Objective Varus and valgus alignment increase medial and lateral tibiofemoral load. Alignment was associated with tibiofemoral osteoarthritis progression in previous studies; an effect on incident osteoarthritis risk is less certain. This study tested whether alignment influences the risk of incident and progressive radiographic tibiofemoral osteoarthritis. Methods In an observational, longitudinal study of the Multicenter Osteoarthritis Study cohort, full-limb x-rays to measure alignment were acquired at baseline and knee x-rays were acquired at baseline and knee x-rays at baseline and 30 months. Varus alignment was defined as ≤178° and valgus ≥182°. Using logistic regression and generalised estimating equations, the associations of baseline alignment and incident osteoarthritis at 30 months (in knees without baseline osteoarthritis) and alignment and osteoarthritis progression (in knees with osteoarthritis) were examined, adjusting. For age, gender, body mass index, injury, laxity and strength, with neutral knees as referent. Results 2958 knees (1752 participants) were without osteoarthritis at baseline. Varus (adjusted OR 1.49, 95% CI 1.06 to 2.10) but not valgus alignment was associated with incident osteoarthritis. 1307 knees (950 participants) had osteoarthritis at baseline. Varus alignment was associated with a greater risk of medial osteoarthritis progression (adjusted OR 3.59, 95% CI 2.62 to 4.92) and a reduced risk of lateral progression, and valgus with a greater risk of lateral progression (adjusted OR 4.85, 95% CI 3.17 to 7.42) and a reduced risk of medial progression. Conclusion Varus but not valgus alignment increased the risk of incident tibiofemoral osteoarthritis. In knees with osteoarthritis, varus and valgus alignment each increased the risk of progression in the biomechanically stressed compartment.
TL;DR: The level of evidence of the association between overweight and developing hand osteoarthritis is moderate according to best-evidence synthesis, and further high-quality cohort or case–control studies are needed to elucidate the role of weight in hand osteOarthritis.
Abstract: Objective: To investigate the association between weight or body mass index (BMI) and the development of hand osteoarthritis. Methods: Systematic review of observational studies. Medical databases were searched up to April 2008. Articles that presented data on the association between weight and hand osteoarthritis were selected. The qualities of these studies were then assessed by two independent reviewers using a 19 criteria scoring system. Using the mean scores of all studies as a cut-off value, the studies were deemed as high or low quality. Study quality and study designs were combined to determine the level of evidence using best-evidence synthesis, which consisted of fi ve levels of evidence. Results: From the 25 studies included, two had cohort, three case-control and 20 cross-sectional study designs. Fifteen studies were considered high-quality studies. Of these high-quality studies, one cohort, two case-control and seven cross-sectional studies showed a positive association between weight or BMI and hand osteoarthritis. Based on three high-quality studies with preferred study designs (one cohort and two case-control) with a positive association, the level of evidence of the association between overweight and developing hand osteoarthritis is moderate. The approximate risk ratio of this association is 1.9. Conclusion: Weight or BMI is associated with the development of hand osteoarthritis. The level of evidence of published studies is moderate according to best-evidence synthesis. Further high-quality cohort or case-control studies are needed to elucidate the role of weight in hand osteoarthritis.
TL;DR: A comparison with other synthetic DMARDs was in favour of MTX, though at the tested doses MTX and leflunomide were equally effective, and MTX was well-tolerated and effective in reducing signs and symptoms, disability and structural damage.
Abstract: Objectives To assess the efficacy and safety of synthetic disease-modifying antirheumatic drugs (DMARDs) in adults with rheumatoid arthritis (RA)—a first step in a European League Against Rheumatism (EULAR) initiative to produce recommendations for the management of RA. Methods A systematic review of the literature using PubMed, Embase and the Cochrane library was performed up to January 2009. All randomised controlled trials (RCTs) reporting the efficacy of synthetic DMARDs (vs placebo or other synthetic DMARDs) on signs and symptoms, disability and/or radiographic structural damage in patients with RA were selected. Studies of biological agents or glucocorticoids were excluded. A pooled effect size (ES) was calculated by meta-analysis. Safety and the occurrence of infections and neoplasia was also assessed. Results 97 RCTs (14 159 patients) were analysed for efficacy. The pooled analysis indicated that methotrexate (MTX) was more efficacious in reducing signs and symptoms, disability and radiographic structural damage than other synthetic DMARDs pooled: ES for swollen joint count (SJC) versus pooled DMARDs=1.42 (95% CI 0.65 to 2.18). Leflunomide appeared to be as effective as MTX. Sulfasalazine and injectable gold were efficacious in reducing signs and symptoms and structural damage. Ciclosporin, minocycline, tacrolimus and hydroxychloroquine showed some efficacy in reducing SJC. Auranofin and D-penicillamine showed no significant superiority over placebo. The risks of cancer and of infection were increased with cyclophosphamide and azathioprine. Conclusions MTX was well-tolerated and effective in reducing signs and symptoms, disability and structural damage. A comparison with other synthetic DMARDs was in favour of MTX, though at the tested doses MTX and leflunomide were equally effective.
TL;DR: The greatest threat to patients with AAV in the first year of therapy is from adverse events rather than active vasculitis, and the accumulation of adverse events should prompt increased awareness that the patient is at high risk of death.
Abstract: Objective To contrast the effect of the burden of vasculitis activity with the burden of adverse events on 1-year mortality of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods This study assessed the outcome and adverse events in patients prospectively recruited to four European AAV clinical trials. Data on 524 patients with newly diagnosed AAV were included. The burden of adverse events was quantified using a severity score for leucopenia, infection and other adverse events, with an additional weighting for follow-up duration. A ‘combined burden of events’ (CBOE) score was generated for each patient by summing the individual scores. Vasculitis severity was quantified using the Birmingham vasculitis activity score and glomerular filtration rate (GFR). Results 1-year mortality probability was 11.1%; 59% and 14% of deaths were caused by therapy-associated adverse events and active vasculitis, respectively. Using Cox regression analysis, infection score (p Conclusions The greatest threat to patients with AAV in the first year of therapy is from adverse events rather than active vasculitis. The accumulation of adverse events, monitored using this scoring method, should prompt increased awareness that the patient is at high risk of death.
University of Pisa1, Dresden University of Technology2, University of Crete3, University of Texas at Austin4, University of Barcelona5, University of Padua6, Cambridge University Hospitals NHS Foundation Trust7, St Thomas' Hospital8, University of Münster9, University of Birmingham10, Johns Hopkins University11, University of Düsseldorf12, Tel Aviv Sourasky Medical Center13, Sheba Medical Center14, Tel Aviv University15, Medical University of Vienna16, Karolinska Institutet17, National Institutes of Health18, University of Pennsylvania19
TL;DR: A ‘core set’ of minimal variables for the assessment and monitoring of patients with SLE in clinical practice was developed that included some of the recommendations and indications for specific organ assessments that were viewed as part of good clinical practice.
Abstract: Objectives: To develop recommendations for monitoring patients with systemic lupus erythematosus (SLE) in clinical practice and observational studies and to develop a standardised core set of variables to monitor SLE. Methods: We followed the European League Against Rheumatism (EULAR) standardised procedures for guideline development. The following techniques were applied: nominal groups, Delphi surveys for prioritisation, small group discussion, systematic literature review and two Delphi rounds to obtain agreement. The panel included rheumatologists, internists, dermatologists, a nephrologist and an expert related to national research agencies. The level of evidence and grading of recommendations were determined according to the Levels of Evidence and Grades of Recommendations of the Oxford Centre for Evidence-Based Medicine. Results: A total of 10 recommendations have been developed, covering the following aspects: patient assessment, cardiovascular risk factors, other risk factors (osteoporosis, cancer), infection risk (screening, vaccination, monitoring), frequency of assessments, laboratory tests, mucocutaneous involvement, kidney monitoring, neuropsychological manifestations and ophthalmology assessment. A ‘core set’ of minimal variables for the assessment and monitoring of patients with SLE in clinical practice was developed that included some of the recommendations. In addition to the recommendations, indications for specifi c organ assessments that were viewed as part of good clinical practice were discussed and included in the fl ow chart. Conclusions: A set of recommendations for monitoring patients with SLE in routine clinical practice has been developed. The use of a standardised core set to monitor patients with SLE should facilitate clinical practice, as well as the quality control of care for patients with SLE, and the collection and comparison of data in observational studies.
TL;DR: Rituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48, and no significant differences in either clinical or safety outcomes were apparent between the rituxIMab doses.
Abstract: Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naive to prior biological treatment. Methods Patients with active disease on stable MTX (10–25 mg/week) were randomised to rituximab 2×500 mg (n=168), rituximab 2×1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) ≥2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2×500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. Results At week 24, both doses of rituximab showed statistically superior efficacy (p Conclusions Rituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses.
TL;DR: Epitope spreading with an increase in the recognition of citrullinated antigens occurs before the onset of RA, and immunological differences in ACPA fine specificity between UA–UA patients and UA–RA patients are associated with the future disease course.
Abstract: Background Anti-citrullinated protein antibodies (ACPA) are the most predictive factor for the development of rheumatoid arthritis (RA).
Objective To investigate whether the recognition of citrulli ...
TL;DR: In a cohort of patients with SLE originating from Israel and Europe vitamin D serum concentrations were found to be inversely related to disease activity.
Abstract: Background Low serum vitamin D concentrations have been reported in several autoimmune disorders. Objective To assess whether low serum vitamin D concentrations are related to disease activity of patients with systemic lupus erythematosus (SLE). Methods 378 patients from several European and Israeli cohorts were pooled and their disease activity was measured by two different methods: 278 patients had SLE disease activity-2000 (SLEDAI-2K) scores and 100 patients had European Consensus Lupus Activity Measurement (ECLAM) scores. In order to combine the two systems the scores were converted into standardised values (z-scores), enabling univariate summary statistics for the two variables (SLEDAI-2K and ECLAM). The commercial kit, LIAISON 25-OH vitamin D assay (310900-Diasorin) was used to measure serum concentration of 25-OH vitamin D in 378 patients with SLE. Results A significant negative correlation was demonstrated between the serum concentration of vitamin D and the standardised values (z-scores) of disease activity scores as measured by the SLEDAI-2K and ECLAM scales (Pearson9s correlation coefficient r=−0.12, p=0.018). Conclusions In a cohort of patients with SLE originating from Israel and Europe vitamin D serum concentrations were found to be inversely related to disease activity.
TL;DR: The understanding of the pathogenesis and optimal therapeutics for rheumatoid arthritis has advanced remarkably over the last decade, particularly the outcomes of genome-wide scans which have provided an increasingly robust appraisal of the complex genetics that underpin RA.
Abstract: The understanding of the pathogenesis and optimal therapeutics for rheumatoid arthritis (RA) has advanced remarkably over the last decade. This review highlights these key advances, particularly the outcomes of genome-wide scans which have provided an increasingly robust appraisal of the complex genetics that underpin RA. Such observations are placed in pathogenetic context, particularly concerning the breach of tolerance that presages synovitis and the mechanisms that subserve chronicity. The key therapeutic strategies and treatment agents, both conventional and biological, now available to effectively manage the disease are described. Throughout the review, emphasis is placed on unanswered questions and challenges in this exciting field.