Jakub Zavada

2016 updated EULAR evidence-based recommendations for the management of gout

Background New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. Methods The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. Results Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. Conclusions These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.

Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.(ClinicalTrials.gov identifier: NCT00976300) Lupus (2010) 19, 1281—1289.

Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers

Objectives Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. Methods Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were calculated across countries by taking the size of the register into account. Results Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab-exposed patients were 1.1 (95% CI 0.9 to 1.4), 1.2 (0.99 to 1.6) and 1.3 (0.6 to 2.6), respectively. Incidence rates in tocilizumab and abatacept-exposed patients were also not significantly increased. IRR versus biologic-naïve patients were: TNFi 1.1 (95% CI 0.8 to 1.6); rituximab 1.2 (0.5 to 2.9). Conclusions This large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi.

Seroprevalence and specificity of NMO-IgG (anti-aquaporin 4 antibodies) in patients with neuropsychiatric systemic lupus erythematosus.

Neuropsychiatric manifestations are present in 30–40% of patients with systemic lupus erythematosus (SLE). Recently, antibodies to aquaporin-4 (termed AQP4-Ab, or NMO-IgG), a water channel protein, were reported to be present in a subset of patients with SLE and neurological involvement. To evaluate the syndrome specificity and prevalence of serum NMO-IgG/anti-AQP4 antibodies in patients with neuropsychiatric systemic lupus erythematosus (NPSLE). Sera of 76 patients with SLE and neurological symptoms, 50 of whom met the ACR case definitions of NPSLE, were tested for AQP4-Ab in an indirect immunofluorescence assay employing HEK293 cells transfected with recombinant human AQP4. Only one of the examined sera was positive for NMO-IgG/AQP4-Ab. This patient suffered from TM, ranging over two vertebral segments on spinal MRI. None of the 75 NPSLE without TM was found to be seropositive for NMO-IgG/AQP4-Ab. NMO-IgG/AQP4-Ab in NPSLE were present only in a patient with TM and were not detectable in NPSLE patients with other neurological manifestations. Testing for NMO-IgG/AQP4-Ab positivity should be considered in patients presenting with SLE and TM. Non-longitudinally extensive lesions do no not exclude NMO-IgG/AQP4-Ab in patients presenting with SLE and TM.

Serum calprotectin (S100A8/9): an independent predictor of ultrasound synovitis in patients with rheumatoid arthritis.

IntroductionCalprotectin, a heterodimeric complex of S100A8/9 (MRP8/14), has been proposed as an important serum biomarker that reflects disease activity and structural joint damage in rheumatoid arthritis (RA). The objective of this cross-sectional study was to test the hypothesis that calprotectin is associated with clinical and ultrasound-determined disease activity in patients with RA.MethodsA total of 37 patients with RA (including 24 females, a mean disease duration of 20 months) underwent a clinical examination and 7-joint ultrasound score (German US-7) of the clinically dominant hand and foot to assess synovitis by grey-scale (GS) and synovial vascularity by power Doppler (PD) ultrasound using semiquantitative 0–3 grading. The levels of serum calprotectin and C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were determined at the time of the ultrasound assessment. We analysed the relationship between serum calprotectin level, traditional inflammatory markers, and ultrasound-determined synovitis.ResultsThe levels of serum calprotectin were significantly correlated with swollen joint count (r = 0.465, p < 0.005), DAS28-ESR (r = 0.430, p < 0.01), ESR (r = 0.370, p < 0.05) and, in particular, CRP (r = 0.629, p < 0.001). Calprotectin was significantly associated with GS (r = 0.359, p < 0.05) and PD synovitis scores (r = 0.497, p < 0.005). Using multivariate regression analysis, calprotectin, adjusted for age and sex, was a better predictor of PD synovitis score (R2 = 0.765, p < 0.001) than CRP (R2 = 0.496, p < 0.001).ConclusionsThe serum levels of calprotectin are significantly associated with clinical, laboratory and ultrasound assessments of RA disease activity. These results suggest that calprotectin might be superior to CRP for monitoring ultrasound-determined synovial inflammation in RA patients.

Circulating Endothelial Progenitor Cells in Patients with ANCA-Associated Vasculitis

Background/Aims: Bone marrow-derived endothelial progenitor cells (EPCs) are believed to contribute to endothelial repair after vascular damage. To investigate the potential for microvascular repair in patients with ANCA-associated vasculitis (AAV), we conducted a cross-sectional study determining the number of circulating EPCs in patients with AAV, chronic uremia, atherosclerosis, and in healthy volunteers. Methods: The number of circulating EPCs was determined by colony-forming assay in 41 patients with AAV, 15 hemodialysis patients (without vasculitis), 13 patients with peripheral arterial occlusive disease (PAOD), and 25 healthy controls. Results: Patients with AAV had a significantly lower number of CFU-Hill than healthy subjects (median 0.3 vs. 19.5 CFU-Hill/ml blood, p < 0.0001), but not than patients on hemodialysis or with PAOD. Neither institution of treatment nor entering remission increased the number of EPCs in AAV patients. The number of EPCs did not correlate with markers of disease activity. AAV patients with glomerular filtration rate <15 ml/min had an even lower number of circulating EPCs than patients with better preserved renal function (median 0.05 vs. 1.2 CFU-Hill/ml, p = 0.015) and patients with anti-MPO positivity had a trend towards a higher number of EPCs than patients with anti-PR3 antibodies (median 3.1 vs. 0.18 CFU-Hill/ml, p = 0.06). Conclusion: Patients with AAV have a significant and persistent deficiency of circulating EPCs. A low number of EPCs could reflect an impaired mechanism of vascular repair and may contribute to repeated relapses in these patients.

A tailored approach to reduce dose of anti-TNF drugs may be equally effective, but substantially less costly than standard dosing in patients with ankylosing spondylitis over 1 year: a propensity score-matched cohort study

Objective To compare the effectiveness, safety and costs of standard versus individually tailored reduced doses of anti-tumour necrosis factor (TNF) drugs in patients with ankylosing spondylitis (AS) after achieving low-disease activity. Methods This was a single-centre prospective observational study performed within the ATTRA registry. The anti-TNF dose tapering strategy was chosen by treating physicians, without prespecified protocol. We used propensity score (PS) methodology to identify two cohorts of patients matched for relevant baseline characteristics who were treated with either reduced (n=53) or standard (n=83) doses of TNF inhibitors. One-year outcomes and costs of anti-TNF drugs were compared between both PS-matched cohorts. Results In the reduced dosing group, the median dose of TNF inhibitor corresponded to 0.67 and 0.5 of the standard dose initially and at 12 months respectively, and 21% of patients required return to standard dosing regimen. The mean change per year in Bath Ankylosing Spondylitis Activity Index, C-reactive protein , Health Assessment Questionnaire Disability Index and Bath AS functional index, as well as quality-adjusted life-year area under the curve were no different between both groups. The HR (95% CI) of reduced versus standard dosing group for relapse and any adverse event was 1.46 (0.66 to 3.19) and 0.56 (0.22 to 1.44), respectively. Mean difference (95% CI) in cost of anti-TNF drugs was €−4214 (−4707 to −3701) per year of treatment in favour of reduced dosing strategy. Conclusions In patients with AS after reaching low-disease activity, a tailored approach to reduce doses of anti-TNF drugs produced similar clinical outcomes at 1 year, but was substantially less costly.

SAT0532 Updated Eular Evidence-Based Recommendations for the Diagnosis of Gout

Background Gout has become the most common inflammatory arthritis but is still frequently misdiagnosed. New data on imaging and clinical diagnosis have become available since publication of the first EULAR recommendations for the diagnosis of gout in 2006. This has prompted a systematic review and update of the 2006 recommendations. Objectives To develop updated evidence-based recommendations for the diagnosis of gout Methods The 2014 EULAR task force comprised 15 rheumatologists, 1 radiologist, 2 GPs, 2 patients and 2 experts in methodology from 12 European countries. The expert group first voted to determine whether each of the 2006 recommendations for diagnosis should be retained, modified or deleted. MEDLINE, EMBASE and Cochrane Library reports were searched systematically to obtain research evidence from 2005 to 2013 on all aspects of the diagnosis of gout. Internal and external validity of the articles was assessed. The quality of evidence was categorised according to GRADE. The task force was presented with a synopsis of this literature review and generated a first draft of key recommendations after a two-day meeting. Final recommendations were agreed using a Delphi consensus approach. The level of agreement to each recommendation was assessed using EULAR numeral rating scales. Results A search for crystals in synovial fluid (SF) or tophus aspirates was recommended in every person with suspected gout, because demonstration of monosodium urate (MSU) crystals allows a definitive diagnosis of gout. SF should also be examined for crystals in any arthritis of unknown aetiology. There was consensus that a number of suggestive clinical features supported a clinical diagnosis of gout. These are: mono articular involvement of a foot or ankle joint (especially the first MTP); previous episodes of similar acute arthritis; rapid onset of severe pain and swelling (at its worst in <24 h); erythema; male gender; and associated cardiovascular diseases and hyperuricaemia. When crystal identification is not possible, it was recommended that any atypical presentation should be investigated by imaging, in particular with ultrasound to seek features suggestive of urate deposits (double contour sign and tophi). There was consensus a that a diagnosis of gout should not be based on the presence of hyperuricaemia alone. There was also a strong recommendation that all persons with gout should be systematically assessed for the presence of associated co-morbidities and risk factors for cardiovascular disease, as well as for risk factors for chronic hyperuricaemia. Conclusions Eight updated, evidence-based, expert consensus recommendations for the diagnosis of gout are proposed. Disclosure of Interest P. Richette Speakers bureau: Ménarini, Ipsen, Savient, Novartis, Astra-ZenecaM, E. Pascual Speakers bureau: Menarini, Savient, Novartis, Astra Zaneca, M. Doherty Speakers bureau: Menarini, Ardea and Novartis, V. Barskova: None declared, F. Becce: None declared, M. Coyfish: None declared, H. Janssens: None declared, T. Jansen Speakers bureau: Ménarini, F. Lioté Speakers bureau: Novartis, Ipsen, Menarini, SOBI, Mayolly-Spindler, Astra-Zeneca, Ardea, Savient, C. Mallen: None declared, G. Nuki Speakers bureau: Ipsen, Menarini, Novartis and Savient., F. Perez-Ruiz Speakers bureau: Astra-Zeneca, Menarini, Metabolex, Novartis, Pfizer, SOBI, J. Pimentão Speakers bureau: Ménarini, T. Piwell: None declared, L. Punzi Speakers bureau: Ménarini, A. So Speakers bureau: Novartis, SOBI, Astra-Zeneca and Menarini, A.-K. Tausche Speakers bureau: Menarini, Savient, Novartis, Sobi, Ardea Bioscience, T. Uhlig: None declared, J. Zavada Speakers bureau: Ménarini, Novartis, W. Zhang Speakers bureau: Savient, F. Tubach: None declared, T. Bardin Speakers bureau: Ménarini, Ipsen, Savient, Novartis, Astra-Zeneca, SOBI DOI 10.1136/annrheumdis-2014-eular.5546

Extended follow-up of the CYCLOFA-LUNE trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide or on cyclosporine A.

Objective To evaluate the extended follow-up of the CYCLOFA-LUNE trial, a randomized prospective trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide (CPH) or cyclosporine A (CyA). Patients and methods Data for kidney function and adverse events were collected by a cross-sectional survey for 38 of 40 patients initially randomized in the CYCLOFA-LUNE trial. Results The median follow-up time was 7.7 years (range 5.0–10.3). Rates of renal impairment and end-stage renal disease, adverse events (death, cardiovascular event, tumor, premature menopause) did not differ between the CPH and CyA group, nor did mean serum creatinine, 24 h proteinuria and SLICC damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. Conclusion An immunosuppressive regimen based on CyA achieved similar clinical results to that based on CPH in the very long term.

Intracellular cytokine production in ANCA-associated vasculitis: low levels of interleukin-10 in remission are associated with a higher relapse rate in the long-term follow-up.

BACKGROUND AND AIMS Dysregulation of cell-mediated immune response likely plays a role in the pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), but it has not yet been fully established. The aim of this study was to assess the intracellular cytokine production in patients with AAV at different stages of the disease, in particular, in relation to the long-term prognosis. METHODS We included 69 patients with AAV and 24 healthy controls. Using flow cytometry, the following intracellular cytokines (IC) were measured in all patients: interferon-gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin-2 and interleukin-4 in CD3+T cells and interleukin-10 (IL-10) and interleukin 12 (IL-12) in monocytes. Patients were then prospectively followed for a median of 43 months and cytokine production was related to the long-term prognosis. RESULTS When compared to healthy controls, increased IL-12 production was observed in AAV patients, both active (p<0.01) and in remission (p<0.05). In remission, increased IFN-gamma production was also found (p<0.01). IL-10 production was higher in active patients than in patients in remission (p<0.05) but did not differ from controls. Patients in remission who developed a relapse during follow-up had significantly lower IL-10 production than those without relapse (p<0.01). Results of this prospective study of IC production in AAV confirm findings of previous studies measuring circulating cytokine levels. CONCLUSIONS Activation of the immune system in AAV patients is noticeable even in remission. Patients with AAV display increased IL-12 production, which seems to be counterbalanced by IL-10. Low IL-10 levels in remission are associated with a higher relapse rate in the long-term follow-up.