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Objectives The underlying structural brain correlates of neuropsychiatric involvement in systemic lupus erythematosus (NPSLE) remain unclear, thus hindering correct diagnosis. We compared brain tissue volumes between a clinically well-defined cohort of patients with NPSLE and SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). Within the NPSLE patients, we also examined differences between patients with two distinct disease phenotypes: ischemic and inflammatory. Methods In this prospective (May 2007 to April 2015) cohort study, we included 38 NPSLE patients (26 inflammatory and 12 ischemic) and 117 non-NPSLE patients. All patients underwent a 3-T brain MRI scan that was used to automatically determine white matter, grey matter, white matter hyperintensities (WMH) and total brain volumes. Group differences in brain tissue volumes were studied with linear regression analyses corrected for age, gender, and total intracranial volume and expressed as B values and 95% confidence intervals. Results NPSLE patients showed higher WMH volume compared to non-NPSLE patients (p = 0.004). NPSLE inflammatory patients showed lower total brain (p = 0.014) and white matter volumes (p = 0.020), and higher WMH volume (p = 0.002) compared to non-NPSLE patients. Additionally, NPSLE inflammatory patients showed lower white matter (p = 0.020) and total brain volumes (p = 0.038) compared to NPSLE ischemic patients. Conclusion We showed that different phenotypes of NPSLE were related to distinct patterns of underlying structural brain MRI changes. Especially the inflammatory phenotype of NPSLE was associated with the most pronounced brain volume changes, which might facilitate the diagnostic process in SLE patients with neuropsychiatric symptoms. Key Points • Neuropsychiatric systemic lupus erythematosus (NPSLE) patients showed a higher WMH volume compared to SLE patients with neuropsychiatric syndromes not attributed to SLE (non-NPSLE). • NPSLE patients with inflammatory phenotype showed a lower total brain and white matter volume, and a higher volume of white matter hyperintensities, compared to non-NPSLE patients. • NPSLE patients with inflammatory phenotype showed lower white matter and total brain volumes compared to NPSLE patients with ischemic phenotype.

Objectives: To analyze the prevalence, incidence, survival and contribution on mortality of major central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). Methods: Patients fulfilling the SLE 1997 ACR classification criteria from the multicentre, retrospective RELESSER-TRANS (Spanish Society of Rheumatology Lupus Register) were included. Prevalence, incidence and survival rates of major CNS neuropsychiatric (NP)-SLE as a group and the individual NP manifestations cere-brovascular disease (CVD), seizure, psychosis, organic brain syndrome and transverse myelitis were calculated. Furthermore, the contribution of these manifestations on mortality was analysed in Cox regression models adjusted for confounders. Results: A total of 3591 SLE patients were included. Of them, 412 (11.5%) developed a total of 522 major CNS NP-SLE manifestations. 61 patients (12%) with major CNS NP-SLE died. The annual mortality rate for patients with and without ever major CNS NP-SLE was 10.8% vs 3.8%, respectively. Individually, CVD (14%) and organic brain syndrome (15.5%) showed the highest mortality rates. The 10% mortality rate for patients with and without ever major CNS NP-SLE was reached after 12.3 vs 22.8 years, respectively. CVD (9.8 years) and organic brain syndrome (7.1 years) reached the 10% mortality rate earlier than other major CNS NP-SLE manifestations. Major CNS NP-SLE (HR 1.85, 1.29-2.67) and more specifically CVD (HR 2.17, 1.41-3.33) and organic brain syndrome (HR 2.11, 1.19-3.74) accounted as independent prognostic factors for poor survival. Conclusion: The presentation of major CNS NP-SLE during the disease course contributes to a higher mortality, which may differ depending on the individual NP manifestation. CVD and organic brain syndrome are associated with the highest mortality rates.

Highlights • QSM was hypothesized to reflect neuroinflammation in neuropsychiatric SLE. • Susceptibility values of the basal ganglia are not changed in SLE and NPSLE. • Neither disease activity nor damage due to SLE correlated with susceptibility values. • Postmortem brain tissue of SLE patients showed no increase of iron compared to controls., Systemic lupus erythematosus (SLE) is an auto-immune disease characterized by multi-organ involvement. Although uncommon, central nervous system involvement in SLE, termed neuropsychiatric SLE (NPSLE), is not an exception. Current knowledge on underlying pathogenic mechanisms is incomplete, however, neuroinflammation is thought to play a critical role. Evidence from neurodegenerative diseases and multiple sclerosis suggests that neuroinflammation is correlated with brain iron accumulation, making quantitative susceptibility mapping (QSM) a potential hallmark for neuroinflammation in vivo. This study assessed susceptibility values of the thalamus and basal ganglia in (NP)SLE patients and further investigated the in vivo findings with histological analyses of postmortem brain tissue derived from SLE patients. We used a 3T MRI scanner to acquire single-echo T2*-weighted images of 44 SLE patients and 20 age-matched healthy controls. Of the 44 patients with SLE, all had neuropsychiatric complaints, of which 29 were classified as non-NPSLE and 15 as NPSLE (seven as inflammatory NPSLE and eight as ischemic NPSLE). Mean susceptibility values of the thalamus, caudate nucleus, putamen, and globus pallidus were calculated. Formalin-fixed paraffin-embedded post-mortem brain tissue including the putamen and globus pallidus of three additional SLE patients was obtained and stained for iron, microglia and astrocytes. Susceptibility values of SLE patients and age-matched controls showed that iron levels in the thalamus and basal ganglia were not changed due to the disease. No subgroup of SLE showed higher susceptibility values. No correlation was found with disease activity or damage due to SLE. Histological examination of the post-mortem brain showed no increased iron accumulation. Our results suggest that neuroinflammation in NPSLE does not necessarily go hand in hand with iron accumulation, and that the inflammatory pathomechanism in SLE may differ from the one observed in neurodegenerative diseases and in multiple sclerosis.

ObjectivesTo prospectively investigate differences in medium-term patient-reported outcome measures and objective functional outcome measures, between patients receiving and those not receiving intensive short-term immunosuppressive therapy for coronavirus disease 19 (COVID-19)-associated hyperinflammation.MethodsPatients previously included in the COVID-19 High-intensity Immunosuppression in Cytokine storm syndrome (CHIC) study who received immunosuppressive treatment versus standard of care for COVID-19-associated hyperinflammation were invited for follow-up at 3 and 6 months after hospitalisation. At both visits, patients were assessed by a pulmonologist, completed quality of life (QoL) questionnaires and performed pulmonary and exercise function tests. At 3 months, patients additionally completed questionnaires on dyspnoea, anxiety, depression and trauma. Outcomes were compared between patients receiving and those not receiving intensive short-term immunosuppressive therapy for COVID-19-associated hyperinflammation.Results131 (66.5%) patients survived hospitalisation due to COVID-19-associated hyperinflammation and 118 (90.1%) were included. QoL questionnaires, pulmonary- and exercise function tests showed improvement between 3 and 6 months after discharge, which was similar in both groups. Assessed patients reached levels that were close to levels predicted from the normal population. In contrast, diffusing capacity of the lung for carbon monoxide was disturbed in both groups: 69.6% predicted (SD 16.2) and 73.5% predicted (SD 16.5) in control group and treated group, respectively.ConclusionsNo differences in medium-term outcomes are demonstrated in survivors of COVID-19-associated hyperinflammation treated or not treated with methylprednisolone with or without tocilizumab during the acute phase. Short-term benefits of this therapy, as showed in the baseline CHIC study analysis, are thus not hampered by medium-term adverse events.

ObjectivesTo update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19.MethodsAccording to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting.ResultsWe updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapyConclusionsGrowing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.

Introduction Les formes sévères de COVID-19 comportent à une hyperinflammation systémique intense ; ce qui a justifié des essais thérapeutiques avec des immunomodulateurs régulièrement utilisés chez les patients atteints de maladies systémiques auto-immunes ou inflammatoires Depuis février 2021 où les premières recommandations EULAR sur l’utilisation de thérapeutiques immunomodulatrices dans le COVID-19 ont été publiées [1], de nouveaux essais thérapeutiques ont été réalisés ce qui rend nécessaire une mise à jour ces recommandations. Matériels et méthodes Selon les procédures standardisées de l’EULAR [2], les résultats d’une revue de la littérature systémique réalisée jusqu’au 15 décembre 2020 puis mise à jour jusqu’au 14 juillet 2021 incluant tous types d’études ont été présentés à un groupe de travail multidisciplinaire composé d’experts internationaux comprenant des rhumatologues, des immunologistes translationnels, des hématologues, des pédiatres, des patients et des professionnels de la santé. La mise à jour des recommandations a été discutée et votée par l’ensemble du panel d’experts sur la base des résultats présentés, principalement des essais randomisés contrôlés (ECT) sur différents traitements immunomodulateurs. Résultats La mise à jour comprend deux principes généraux et dix recommandations. Les recommandations concernent uniquement la prise en charge des patients présentant des formes de COVID-19 modérées à sévères ou critiques, faute de preuves suffisantes avec très peu d’ECT concernant les patients asymptomatiques et ceux avec des formes légères de la maladie. Les molécules suivantes ont montré une efficacité dans le traitement de formes modérées à sévères ou critiques du COVID-19. L’association de glucocorticoïdes et de tocilizumab est bénéfique dans les cas de COVID-19 nécessitant une oxygénothérapie et dans les cas critiques de COVID-19. L’utilisation d’inhibiteurs de Janus kinase (baricitinib et tofacitinib) et peut-être d’Ac anti-GM-CSF est prometteuse dans les mêmes populations. Les anticorps monoclonaux anti-SARS-CoV-2 et l’utilisation de plasma convalescent pourraient trouver une application dans les phases précoces de la maladie et dans certains sous-groupes de patients immunodéprimés. D’autres immunomodulateurs comme l’hydroxychloroquine, la colchicine ou l’anakinra n’ont pas démontré leur efficacité sur la mortalité et ou sur l’aggravation clinique (évolution vers une détresse respiratoire), quel que soit le stade de la maladie. Conclusion Un nombre grandissant d’ECT soutiennent l’efficacité de l’association de glucocorticoïdes et d’autres agents immunomodulateurs tels que le tocilizumab dans le traitement de formes modérée à sévère et critique du COVID-19. De plus, certaines études en cours pourraient confirmer l’efficacité potentielle d’autres approches thérapeutiques comme les inhibiteurs de JAK ou les Ac anti-GM-CSF. L’implication des rhumatologues, en tant qu’experts des maladies inflammatoires et auto-immunes systémiques et des traitements immunomodulateurs est nécessaire dans le design des nouveaux essais cliniques et dans l’élaboration de nouvelles recommandations pour la prise en charge du COVID-19.

Objectives COVID-19 is an ongoing global pandemic. There is an urgent need for identification and understanding of clinical and laboratory parameters related to progression towards a severe and fatal form of this illness, often preceded by a so-called cytokine-storm syndrome (CSS). Therefore, we explored the hemocytometric characteristics of COVID-19 patients in relation to the deteriorating clinical condition CSS, using the Sysmex XN-10 hematology analyzer. Methods From March 1st till May 16th, 2020, all patients admitted to our hospital with respiratory complaints and suspected for COVID-19 were included (n=1,140 of whom n=533 COVID-19 positive). The hemocytometric parameters of immunocompetent cells in peripheral blood (neutrophils [NE], lymphocytes [LY] and monocytes [MO]) obtained upon admission to the emergency department (ED) of COVID-19 positive patients were compared with those of the COVID-19 negative ones. Moreover, patients with CSS (n=169) were compared with COVID-19 positive patients without CSS, as well as with COVID-19 negative ones. Results In addition to a significant reduction in leukocytes, thrombocytes and absolute neutrophils, it appeared that lymphocytes-forward scatter (LY-FSC), and reactive lymphocytes (RE-LYMPHO)/leukocytes were higher in COVID-19-positive than negative patients. At the moment of presentation, COVID-19 positive patients with CSS had different neutrophils-side fluorescence (NE-SFL), neutrophils-forward scatter (NE-FSC), LY-FSC, RE-LYMPHO/lymphocytes, antibody-synthesizing (AS)-LYMPHOs, high fluorescence lymphocytes (HFLC), MO-SSC, MO-SFL, and Reactive (RE)-MONOs. Finally, absolute eosinophils, basophils, lymphocytes, monocytes and MO-FSC were lower in patients with CSS. Conclusions Hemocytometric parameters indicative of changes in immunocompetent peripheral blood cells and measured at admission to the ED were associated with COVID-19 with and without CSS.

This work was funded by European League Against Rheumatism (CLI122). PMM is supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). JDI is a NIHR Senior Investigator and his work is supported by the NIHR Newcastle Biomedical Research Centre in Ageing and Long- Term Conditions, and the Research Into Inflammatory Arthritis Centre versus Arthritis. AVR is a member of the paediatric steering committee of RECOVERY, the steering committee of COVINTOC study and the steering committee of baricitinib in COVID-19., Alunno, A., Najm, A., MacHado, P.M., Bertheussen, H., Burmester, G.R., Carubbi, F., De Marco, G., Giacomelli, R., Hermine, O., Isaacs, J.D., Koné-Paut, I., Magro-Checa, C., McInnes, I., Meroni, P.L., Quartuccio, L., Ramanan, A.V., Ramos-Casals, M., Carrio, J.R., Schulze-Koops, H., Stamm, T.A., Tas, S.W., Terrier, B., McGonagle, D.G., Mariette, X.

ObjectivesTo prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only.MethodsFrom 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2–5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation.ResultsAt baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses.ConclusionsA strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.

Several immune mechanisms resembling a hyperinflammatory state have been critically involved in the pathophysiology of severe COVID-19, motivating the use of immunomodulatory therapies in the management of these patients. Various studies have already suggested the efficacy of immunomodulatory medication of treatment for severe COVID-19.1–3 However, concerns have been raised about the impact of these therapies on immunity.4 5 We analysed the presence and levels of antibodies to SARS-CoV-2 in patients recovered from severe COVID-19-associated hyperinflammation after receiving no immunomodulatory therapy, and compared them to patients who received methylprednisolone alone or methylprednisolone followed by tocilizumab. Between March and May 2020, 197 patients were diagnosed with COVID-19-associated hyperinflammation in the Zuyderland Medical Centre. In order to meet the criteria for hyperinflammation, patients had to fulfil specific characteristics that have been previously reported in this journal.1 Up to the 1st of April, patients were treated with standard of care. In April and May, patients were treated according to the COVID-19 high-intensity immunosuppression in cytokine storm syndrome (CHIC) protocol with immunomodulatory therapies. This protocol included …

Background: COVID-19 is associated with cytokine release syndrome (CRS), which contributes to morbidity and mortality Anecdotal reports suggest that CRS impro

Background New ACR-EULAR SLE criteria have been proposed in order to attempt to improve classification for clinical and translational research (1, 2). Objectives We evaluated the performance of the proposed 2017 ACR-EULAR classification criteria in a cohort of SLE patients with neuropsychiatric (NP) symptoms and compared to previous classification criteria. Methods Medical records of patients visiting the NPSLE clinic of the Leiden University Medical Center (LUMC) between 2007-2017 were retrospectively evaluated. The performance of the proposed 2017 ACR-EULAR criteria, the 2012 SLICC criteria and the 1997 ACR criteria was evaluated by calculating sensitivity and specificity. Results 360 patients were included, of which 294 were clinically diagnosed with SLE. The newly proposed 2017 ACR-EULAR showed a sensitivity of 87% (95% CI: 83-91%) and a specificity of 74% (95% CI: 62-84%), as shown in Table 1. The 2012 SLICC criteria had a sensitivity of 85% (95% CI: 80-89%) and a specificity of 76% (95% CI: 64-85%). The 1997 ACR criteria had a sensitivity of 89% (95% CI: 85-92%) and a specificity of 89% (95% CI: 80-96%). Sixty out of 294 patients fulfilled the proposed NP domain (delirium/psychosis/epilepsy). Using more specific criteria for NP symptoms related to SLE, as previously proposed by Bortoluzzi et al. (3), only 37 patients fulfilled this domain. However, this did not improve specificity, which remained 74% (95% CI: 62-84%). In addition, the performance of the newly proposed criteria was evaluated including patients with more than 10 points, but negative ANA. This led to an increase of sensitivity to 90% (95% CI 86-94%), but also did not influence specificity. Conclusion In a cohort of SLE patients with NP symptoms, the proposed 2017 ACR-EULAR classification criteria showed similar sensitivity as the 1997 ACR and the SLICC 2012 criteria, but lower specificity. Including ANA negative patients improved sensitivity. References [1] 2018ACR/ARHP Annual Meeting Abstract Supplement. Arthritis Rheumatol, 2018.70Suppl 9: p.1-355. [2] Tedeschi SK, et al., Developing and Refining New Candidate Criteria for Systemic Lupus Erythematosus Classification: An International Collaboration. Arthritis Care Res (Hoboken), 2018. 70(4): p.571-581. [3] Bortoluzzi A, et al., Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus. Rheumatology (Oxford), 2015. 54(5): p.891-8. Disclosure of Interests Rory Monahan: None declared, H.J.L. Beaart: None declared, Maka Gegeneva: None declared, E.G. Brilman: None declared, L.J.J. Beaart- van de Voorde: None declared, Cesar Magro Checa: None declared, Thomas Huizinga Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, GSK, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience Inc., Nycomed, Boeringher, Takeda, Zydus, Epirus, Eli Lilly, G.M. Steup-Beekman: None declared

Objective: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc–RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc–RA loci through an interdisease meta–genome-wide association (meta-GWAS) strategy. Methods: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case–control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. Results: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10−6) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc–RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10−12). Analysis of the biologic relevance of the known SSc–RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. Conclusion: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.

OBJECTIVE To assess white matter (WM) and gray matter (GM) magnetization transfer ratio histogram peak heights (MTR-HPHs) in different subsets of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) who have unremarkable findings on 3T magnetic resonance imaging of the brain and to evaluate whether these values could be used to highlight different clinically suspected underlying pathogenic processes or identify the clinical NPSLE status or whether they could be associated with a specific NPSLE syndrome. METHODS Sixty-four SLE patients with neuropsychiatric symptoms were included. The initial NPSLE diagnosis and suspected underlying pathogenic process were established by multidisciplinary evaluation. The final diagnosis was made after also considering the disease course 6-18 months later. Thirty-three patients with central nervous system (CNS) NPSLE and 31 SLE patients with neuropsychiatric symptoms unrelated to SLE (non-SLE-related NP) were included. Twenty SLE patients without neuropsychiatric symptoms and 36 healthy control subjects were included for comparison. Differences in the WM and GM mean MTR-HPHs and between the different NPSLE subgroups (CNS NPSLE diagnosis, NPSLE phenotype [inflammatory or ischemic], and clinical changes after treatment) and the relationship to NPSLE syndromes were evaluated. RESULTS Patients with inflammatory NPSLE had significantly lower WM MTR-HPHs than did the healthy controls, the SLE patients, and the non-SLE-related NP patients. Cognitive disorder, mood disorder, and psychosis were related to lower WM MTR-HPH values and cerebrovascular symptoms to higher values. Furthermore, the mean MTR-HPHs in the WM increased when the clinical status of the NPSLE patients improved. CONCLUSION Measurement of MTR-HPH of the WM has the potential to identify inflammatory NPSLE with CNS involvement. This finding underscores the usefulness of this technique for the detection of cerebral changes in NPSLE patients and for the assessment of clinical changes after treatment.

Key messages #### What is already known about this subject? #### What does this study add? #### How might this impact on clinical practice? Systemic lupus erythematosus (SLE) is a heterogenic connective tissue disease with a broad spectrum of clinical and laboratory manifestations. Due to this heterogeneity, SLE remains challenging to diagnose in clinical practice. In order to create a more homogeneous patient group, the American College of Rheumatology (ACR) developed classification criteria for research purposes in 1972.1 These criteria were revised in 1982 and 1997.2 3 In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) developed and validated new SLE classification criteria.4 The SLICC 2012 criteria performed better than the revised 1997 ACR criteria in terms of sensitivity (97% vs 83%), but were less specific (84% vs 96%).4 Recently, new ACR–EULAR criteria have been proposed in order to improve specificity, while keeping the optimal sensitivity of the SLICC 2012 criteria. Several new elements were added, including the presence of antinuclear antibodies (ANA) as entry criterium, weighted scores for each criterium and domain scores.5–7 It is currently unknown how these criteria perform in patients with SLE with neuropsychiatric (NP) symptoms, one of the least understood manifestations of SLE. Therefore, we aimed to evaluate the performance of the proposed ACR–EULAR criteria in our cohort of patients with SLE presenting with NP symptoms. A retrospective cohort study was performed using electronic medical records of patients referred to the NPSLE clinic in the Leiden …

Research in rheumatoid arthritis (RA) is increasingly focused on the discovery of biomarkers that could enable personalized treatments. The genetic biomarkers associated with the response to TNF inhibitors (TNFi) are among the most studied. They include 12 SNPs exhibiting promising results in the three largest genome-wide association studies (GWAS). However, they still require further validation. With this aim, we assessed their association with response to TNFi in a replication study, and a meta-analysis summarizing all non-redundant data. The replication involved 755 patients with RA that were treated for the first time with a biologic drug, which was either infliximab (n = 397), etanercept (n = 155) or adalimumab (n = 203). Their DNA samples were successfully genotyped with a single-base extension multiplex method. Lamentably, none of the 12 SNPs was associated with response to the TNFi in the replication study (p > 0.05). However, a drug-stratified exploratory analysis revealed a significant association of the NUBPL rs2378945 SNP with a poor response to etanercept (B = -0.50, 95% CI = -0.82, -0.17, p = 0.003). In addition, the meta-analysis reinforced the previous association of three SNPs: rs2378945, rs12142623, and rs4651370. In contrast, five of the remaining SNPs were less associated than before, and the other four SNPs were no longer associated with the response to treatment. In summary, our results highlight the complexity of the pharmacogenetics of TNFi in RA showing that it could involve a drug-specific component and clarifying the status of the 12 GWAS-drawn SNPs., This work was supported by the Instituto de Salud Carlos III (ISCIII, Spain) through grants PI14/01651, PI17/01606 and RD16/0012/0014 to AG and PI12/01909 to JJG-R. These grants are partially financed by the European Regional Development Fund of the EU (FEDER). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Background The diagnosis and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) is challenging due to the lack of a diagnostic gold standard and controlled trials. Immunosuppressive therapy is prescribed for immune-mediated NPSLE manifestations, despite little evidence supporting its effectivity. There is increasing evidence for the value of magnetization transfer imaging (MTI) in NPSLE. Recent research has demonstrated that white matter (WM) magnetic transfer ratio histogram peak height (MTR-HPH), a derived-MTI index, is a valuable radiological biomarker for the diagnosis and follow-up in inflammatory NPSLE.1 It remains unknown whether the changes in WM MTR-HPH also correlate with the change in health-related quality of life (QoL) in these patients. Objectives To analyse the correlation between change in WM MTR-HPH and change in QoL in different subsets of NPSLE (inflammatory, ischaemic, non-NPSLE). Methods Patients that visited the Leiden University Medical Centre (LUMC) NPSLE clinic between 2007 and 2015 were included in this study. The attribution process of NP events to SLE and one of its underlying pathogenic mechanisms (ischaemic or inflammatory) was established by multidisciplinary consensus. All patients underwent MRI examination at two different time points and filled in the Short-Form 36 (SF-36). Summary scores were deducted from the SF-36, leading to a Physical Component subscore (PCS) and a Mental Component subscore (MCS) for QoL. Spearman rank correlation coefficient (SR) was used to correlate WM MTR-HPH and the overall difference in change between visits in MCS and PCS. Data was analysed per patient and per event. Results A total of 15 patients (mean age 39.5±14.1 years, 93% female) were included. Thirty-one NPSLE events were present, of which 68% were inflammatory, 13% ischaemic and 19% non-NPSLE events. Average time between visits was 2.9±1.5 years. The per patient analysis showed statistical significant correlation between WM MTR-HPH and MCS change (SR=0.62; p=0.01) and no effect on PCS change (SR=0.09; p=0.76). The per event analysis showed a significant correlation between change in WM MTR-HPH and MCS in inflammatory events (SR=0.56; p=0.01), but not in ischaemic (p=0.20) or non-NPSLE events (p=0.65). No correlation was observed between change in WM MTR-HPH and PCS in any of the subsets (p=0.21, p=0.40 and p=0.91 respectively). Conclusions We are the first to demonstrate a correlation between a radiological biomarker and change in the mental component of QoL in inflammatory NPSLE patients. Our study supplies evidence for the use of immunosuppressive therapy in inflammatory NPSLE and supports the use of this radiological biomarker as an outcome measure for future trials in NPSLE. Reference [1] Magro-Checa C, Ecran E, Wolterbeek R, et al. Changes in White Matter Microstructure Suggest an Inflammatory Origin of Neuropsychiatric Systemic Lupus Erythematosus.Arthritis Rheumatol2016;68(8):1945–1954. Disclosure of Interest None declared

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a generic definition referring to a series of neurological and psychiatric symptoms directly related to systemic lupus erythematosus (SLE). NPSLE includes heterogeneous and rare neuropsychiatric (NP) manifestations involving both the central and peripheral nervous system. Due to the lack of a gold standard, the attribution of NP symptoms to SLE represents a clinical challenge that obligates the strict exclusion of any other potential cause. In the acute setting, management of these patients does not differ from other non-SLE subjects presenting with the same NP manifestation. Afterwards, an individualized therapeutic strategy, depending on the presenting manifestation and severity of symptoms, must be started. Clinical trials in NPSLE are scarce and most of the data are extracted from case series and case reports. High-dose glucocorticoids and intravenous cyclophosphamide remain the cornerstone for patients with severe symptoms that are thought to reflect inflammation or an underlying autoimmune process. Rituximab, intravenous immunoglobulins, or plasmapheresis may be used if response is not achieved. When patients present with mild to moderate NP manifestations, or when maintenance therapy is warranted, azathioprine and mycophenolate may be considered. When symptoms are thought to reflect a thrombotic underlying process, anticoagulation and antiplatelet agents are the mainstay of therapy, especially if antiphospholipid antibodies or antiphospholipid syndrome are present. Recent trials on SLE using new biologicals, based on newly understood SLE mechanisms, have shown promising results. Based on what we currently know about its pathogenesis, it is tempting to speculate how these new therapies may affect the management of NPSLE patients. This article provides a comprehensive and critical review of the literature on the epidemiology, pathophysiology, diagnosis, and management of NPSLE. We describe the most common pharmacological treatments used in NPSLE, based on both a literature search and our expert opinion. The extent to which new drugs in the advanced development of SLE, or the blockade of new targets, may impact future treatment of NPSLE will also be discussed.

Objective. The aim was to investigate the association between autoantibodies (autoAbs) and neuropsychiatric (NP) involvement in patients with SLE and to evaluate whether any autoAb or a combination of these autoAbs could indicate the underlying pathogenic process. Methods. Using a multiplexed protein array for 94 antigens, we compared the serum autoAb profiles of 69 NPSLE patients, 203 SLE patients without NP involvement (non-NPSLE) and 51 healthy controls. Furthermore, we compared the profiles of NPSLE patients with clinical inflammatory (n = 38) and ischaemic (n = 31) NP involvement. Results. In total, 75 IgG and 47 IgM autoAbs were associated with SLE patients in comparison with healthy controls. Comparing NPSLE with non-NPSLE and healthy control sera, 9 IgG (amyloid, cardiolipin, glycoprotein 2, glycoprotein 210, heparin, heparan sulphate, histone H2A, prothrombin protein and vimentin) and 12 IgM (amyloid, cardiolipin, centromere protein A, collagen II, histones H2A and H2B, heparan sulphate, heparin, mitochondrial 2, nuclear Mi-2, nucleoporin 62 and vimentin) autoAbs were present at significantly different levels in NPSLE. The combination of IgG autoAbs against heparan sulphate, histone H2B and vimentin could differentiate NPSLE from non-NPSLE (area under the curve 0.845, 99.97% CI: 0.756, 0.933; P < 0.0001). Compared with non-NPSLE, four IgG and seven IgM autoAbs were significantly associated with inflammatory NPSLE. In ischaemic NPSLE, three IgG and three IgM autoAbs were significantly different from non-NPSLE patients. Conclusion. In our cohort, the presence of high levels of anti-heparan sulphate and anti-histone H2B combined with low levels of anti-vimentin IgG autoAbs is highly suggestive of NPSLE. These results need to be validated in external cohorts.

Objective The objective of this study was to assess whether clinical and patient’s reported outcomes are associated with a different pathophysiological origin of neuropsychiatric events presenting in systemic lupus erythematosus. Methods A total of 232 neuropsychiatric events presenting in 131 systemic lupus erythematosus patients were included. Neuropsychiatric systemic lupus erythematosus diagnosis was established per event by multidisciplinary evaluation. All neuropsychiatric events were divided according to a suspected underlying pathophysiological process into one of the following: non-neuropsychiatric systemic lupus erythematosus related, inflammatory and ischaemic neuropsychiatric systemic lupus erythematosus. The clinical outcome of all neuropsychiatric events was determined by a physician-completed four-point Likert scale. Health-related quality of life was measured with the subscales of the patient-generated Short Form 36 (SF-36) health survey questionnaire. The change between scores at paired visits of all domain scores, mental component summary (SF-36 MCS) and physical component summary (SF-36 PCS) scores were retrospectively calculated and used as patient-reported outcome. The association among these outcomes and the different origin of neuropsychiatric events was obtained using multiple logistic regression analysis. Results The clinical status of 26.8% non-neuropsychiatric systemic lupus erythematosus events, 15.8% ischaemic neuropsychiatric systemic lupus erythematosus and 51.6% inflammatory neuropsychiatric systemic lupus erythematosus improved after re-assessment. Almost all SF-36 domains had a positive change at re-assessment in all groups independently of the origin of neuropsychiatric events. Neuropsychiatric systemic lupus erythematosus ( B = 0.502; p Conclusion Inflammatory neuropsychiatric systemic lupus erythematosus events have better clinical outcome and meaningful improvement in SF-36 MCS than ischaemic neuropsychiatric systemic lupus erythematosus or non-neuropsychiatric systemic lupus erythematosus.

Resume But Evaluer le risque cardiovasculaire (CV) chez les patients atteints de rhumatisme psoriasique (RP) sans maladie CV cliniquement evidente ni de facteurs de risque CV classiques, selon le diagramme SCORE suivant les recommandations de l’EULAR. Methodes Quatre-vingt patients atteints de RP sans antecedent d’evenement CV ni de facteurs de risque d’atherosclerose et 80 controles ont ete inclus. Les donnees demographiques, anthropometriques et clinico-serologiques ont ete evaluees. L’indice national Calibrated Systematic Coronary Risk Evaluation (SCORE) a ete calcule et l’association entre ce SCORE et les donnees clinico-serologiques a ete analysee. Resultats Les patients atteints de RP avaient des parametres de l’inflammation et des valeurs de SCORE plus eleves que les controles (1,99 ± 3,52 vs 1,0 ± 1,74 ; p = 0,028). Selon les definitions SCORE, 71 (89 %) patients avaient un risque CV faible/intermediaire et 9 (11 %) etaient en dessus de la limite du risque eleve. Dans le groupe temoin, 76 (95 %) avaient un risque faible/intermediaire et 4 (5 %) avaient un risque eleve. Cependant, il n’y avait pas de difference en termes de stratification du risque CV entre les deux groupes (p = 0,148). Les patients atteints de RP avec un risque CV eleve avaient une duree d’evolution de la maladie plus elevee (0,001) et un taux plus eleve de triglycerides (p = 0,009). Les patients atteints de RP presentaient une correlation significative entre les valeurs SCORE et la duree d’evolution de la maladie (β = 0,185 ; p = 0,0001) et avec les niveaux moyens annuels de C-reactive protein (CRPm), β = 2,38 ; p = 0,014. Conclusion L’evaluation du risque CV chez les patients atteints de RP sans atteinte CV evidente cliniquement et sans facteurs classiques d’atherosclerose pourrait etre sous-estimee si l’on n’utilise que le diagramme SCORE. Chez ces patients, la duree d’evolution de la maladie et la CRPm pourraient aider a obtenir une meilleure stratification des facteurs de risque CV.

Objective Assess quality of life in patients with systemic lupus erythematosus (SLE) presenting with neuropsychiatric symptoms (neuropsychiatric SLE, NPSLE). Methods Quality of life was assessed using the Short-Form 36 item Health Survey (SF-36) in patients visiting the Leiden NPSLE clinic at baseline and at follow-up. SF-36 subscales and summary scores were calculated and compared with quality of life of the general Dutch population and patients with other chronic diseases. Results At baseline, quality of life was assessed in 248 SLE patients, of whom 98 had NPSLE (39.7%). Follow-up data were available for 104 patients (42%), of whom 64 had NPSLE (61.5%). SLE patients presenting neuropsychiatric symptoms showed a significantly reduced quality of life in all subscales of the SF-36. Quality of life at follow-up showed a significant improvement in physical functioning role ( p = 0.001), social functioning ( p = 0.007), vitality ( p = 0.023), mental health ( p = 0.014) and mental component score ( p = 0.042) in patients with neuropsychiatric symptoms not attributed to SLE, but no significant improvement was seen in patients with NPSLE. Conclusion Quality of life is significantly reduced in patients with SLE presenting neuropsychiatric symptoms compared with the general population and patients with other chronic diseases. Quality of life remains considerably impaired at follow-up. Our results illustrate the need for biopsychosocial care in patients with SLE and neuropsychiatric symptoms.

C1q deficiency is a rare immunodeficiency, which is strongly associated with the development of systemic lupus erythematosus (SLE). A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q. Patients with C1q deficiency mainly present with cutaneous and renal involvement. Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients. This involvement appears to be absent in other deficiencies of early components of the complement classical pathway (C1r/C1s, C2 or C4 deficiencies). We describe a new case with C1q deficiency with a homozygous G34R mutation in C1qC producing LMW-C1q presenting with a severe SLE flare with NP involvement. The serum of this patient contained very low levels of a LMW variant of C1q polypeptides. Cell lysates contained the three chains of C1q but no intact C1q was detected, consistent with the hypothesis of the existence of a LMW-C1q. Furthermore we provide a literature overview of NP-SLE in C1q deficiency and hypothesise about the potential role of C1q in the pathogenesis of NP involvement in these patients. The onset of NP-SLE in C1q deficient individuals is often more severe when compared with complement competent NP-SLE patients. An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis. A defective classical pathway, because of non-functional C1q, does not protect against NP involvement in SLE. The absence of C1q and subsequently some of its biological functions may be associated with more severe NP-SLE.

BACKGROUND: Articular manifestations are common in systemic lupus erythematosus (SLE) whereas erosive disease is not. Antibodies to cyclic citrullinated peptide (anti-CCP) are citrulline-dependent in rheumatoid arthritis (RA), whereas the opposite is suggested in SLE, as reactivity with cyclic arginine peptide (CAP) is typically present. Antibodies targeting carbamylated proteins (anti-CarP) may occur in anti-CCP/rheumatoid factor (RF)-negative cases long before clinical onset of RA. We analysed these antibody specificities in sera from European patients with SLE in relation to phenotypes, smoking habits and imaging data. METHODS: Cases of SLE (n = 441) from Linköping, Sweden, and Leiden, the Netherlands, were classified according to American College of Rheumatology (ACR) and/or Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) criteria. IgG anti-CCP, anti-CAP and anti-CarP were analysed by immunoassays. Radiographic data from 102 Swedish patients were available. RESULTS: There were 16 Linköping (6.8%) and 11 Leiden patients (5.4%) who were anti-CCP-positive, of whom approximately one third were citrulline-dependent: 40/441 (9.1%) were anti-CarP-positive, and 33% of the anti-CarP-positive patients were identified as anti-CCP-positive. No associations were found comparing anti-CCP or anti-CarP with ACR-defined phenotypes, immunologic abnormalities or smoking habits. Radiographically confirmed erosions were found in 10 patients, and were significantly associated with anti-CCP, anti-CarP and RF. Musculoskeletal ultrasonography scores were higher in anti-CCP-positive compared to anti-CCP-negative patients. CONCLUSIONS: In the hitherto largest anti-CarP study in SLE, we demonstrate that anti-CarP is more prevalent than anti-CCP and that the overlap is limited. We obtained some evidence that both autoantibodies seem to be associated with erosivity. Similar pathogenetic mechanisms to those seen in RA may be relevant in a subgroup of SLE cases with a phenotype dominated by arthritis. Funding agencies: County Council of Ostergotland; Swedish Society for Medical Research; Swedish Rheumatism Association; Swedish Society of Medicine; Professor Nanna Svartz foundation; King Gustaf V 80-year foundation; Dutch Arthritis Foundation; IMI JU project, BeTheCure [

Objective: To determine the contribution of reassessment in the attribution process of neuropsychiatric (NP) events to SLE or other aetiologies in a large, prospective and multidisciplinary assessed NPSLE cohort and to compare these results with other available attribution models for NP events occurring in SLE. Methods: Three hundred and four consecutive SLE patients presenting NP events were evaluated. All subjects underwent standardized multidisciplinary medical, neuropsychological, laboratory and radiological examination on the inclusion and reassessment dates. Diagnosis was always established by multidisciplinary consensus. The final diagnosis after reassessment also took into account disease course and response to treatment. These data were compared with currently available attribution models for NP events in SLE. Results: A total of 463 NP events were established. After reassessment, attribution to SLE was discordant in 64 (13.8%) NP events when compared with the first visit. We show that 14.5% of NP events previously attributed to SLE reclassified as non-NPSLE. In 86.4% of these patients immunosuppressive therapy was started after the first visit. When reassessment and available attribution models were compared, NPSLE cases overlapped considerably. Although specificity was high for all comparisons (0.81–0.95), an important variation in sensitivity (0.39–0.83) and agreement estimates (κ = 0.29–0.68) was observed. The Italian algorithm showed the highest sensitivity and specificity (>0.80) and moderate agreement (0.59–0.64). Conclusión: In clinical practice NP events presenting in SLE are too often attributed to an immune-mediated origin. Multidisciplinary reassessment avoids misclassification in NPSLE. Multidisciplinary reassessment is the reference standard in NP events presenting in SLE and cannot be replaced by available attribution models

Systemic lupus erythematosus is an inflammatory autoimmune disease with multi-organ involvement. Central nervous system involvement in systemic lupus erythematosus is common and results in several neurological and psychiatric symptoms that are poorly linked to standard magnetic resonance imaging outcome. Magnetic resonance imaging methods sensitive to tissue microstructural changes, such as diffusion tensor imaging and magnetization transfer imaging, show some correlation with neuropsychiatric systemic lupus erythematosus (NPSLE) symptoms. Histological examination of NPSLE brains reveals presence of cerebral oedema, loss of neurons and myelinated axons, microglial proliferation and reactive astrocytosis, microinfacrts and diffuse ischaemic changes, all of which can affect both diffusion tensor imaging and magnetization transfer imaging in a non-specific manner. Here we investigated the underlying cell-type specific microstructural alterations in the brain of patients with systemic lupus erythematosus with and without a history of central nervous system involvement. We did so combining diffusion tensor imaging with diffusion-weighted magnetic resonance spectroscopy, a powerful tool capable of characterizing cell-specific cytomorphological changes based on diffusion of intracellular metabolites. We used a 7 T magnetic resonance imaging scanner to acquire T1-weighted images, diffusion tensor imaging datasets, and single volume diffusion-weighted magnetic resonance spectroscopy data from the anterior body of the corpus callosum of 13 patients with systemic lupus erythematosus with past NPSLE, 16 patients with systemic lupus erythematosus without past NPSLE, and 19 healthy control subjects. Group comparisons were made between patients with systemic lupus erythematosus with/without past NPSLE and healthy controls on diffusion tensor imaging metrics and on diffusion coefficients of three brain metabolites: the exclusively neuronal/axonal N-acetylaspartate, and the predominantly glial creatine + phosphocreatine and choline compounds. In patients with systemic lupus erythematosus with past NPSLE, significantly higher diffusion tensor imaging mean and radial diffusivities were accompanied by a significantly higher intracellular diffusion of total creatine (0.202 ± 0.032 μm2/ms, P = 0.018) and total choline (0.142 ± 0.031 μm2/ms, P = 0.044) compared to healthy controls (0.171 ± 0.024 μm2/ms, 0.124 ± 0.018 μm2/ms, respectively). Total N-acetylaspartate, total creatine and total choline diffusion values from all patients with systemic lupus erythematosus correlated positively with systemic lupus erythematosus disease activity index score (P = 0.033, P = 0.040, P = 0.008, respectively). Our results indicate that intracellular alterations, and in particular changes in glia, as evidenced by increase in the average diffusivities of total choline and total creatine, correlate with systemic lupus erythematosus activity. The higher diffusivity of total creatine and total choline in patients with NPSLE, as well as the positive correlation of these diffusivities with the systemic lupus erythematosus disease activity index are in line with cytomorphological changes in reactive glia, suggesting that the diffusivities of choline compounds and of total creatine are potentially unique markers for glial reactivity in response to inflammation.

Cardiovascular disease has become the leading cause of mortality in patients with systemic lupus erythematosus (SLE). Accelerated atherosclerosis is considered one of the most important mechanisms implicated in the high cardiovascular (CV) mortality associated with SLE. Atherosclerosis in SLE patients arises from an interaction among classical CV risk factors, inflammatory mediators and factors specific to SLE itself. Consequently, calculating CV risk in these patients is central to decision-making on treatment to prevent CV disease. However, although Systematic COronary Risk Evaluation (SCORE) is recommended by The European League against Rheumatism (EULAR) experts and is widely used by rheumatologists for CV assessment in patients with rheumatoid arthritis and other forms of inflammatory arthritis, CV risk in SLE patients cannot be adequately evaluated with widely used charts for stratifying CV risk. Due to the lack of specific charts, assessment of traditional CV risk factors (smoking, blood pressure, diabetes, body mass index and lipid profile) and the use of validated imaging techniques to detect subclinical atherosclerosis have been proposed for the assessment of vascular disease in SLE patients. Among these techniques, calculating the intima-media thickness of the common carotid arteries measured in the far wall and the presence of plaques in the carotid system have become commonly used indicators of subclinical atherosclerosis. To a certain extent, the use of these methods allows individualized CV assessment and consequently a more useful management strategy, which can decrease CV mortality in SLE patients.

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

OBJECTIVE To assess drug survival and the reasons for switching anti-TNF-α therapy in SpA patients in a Spanish nationwide study. METHODS A cross-sectional study was performed. Sample size was calculated to represent all regions and hospitals throughout the country. Demographic data, patient characteristics and disease activity parameters were obtained. Drug survival and reasons for switching anti-TNF therapy were also recorded. RESULTS A total of 467 SpA patients receiving at least one anti-TNF agent were identified. Among patients who received a first, second and third anti-TNF course, 39.4%, 37.4% and 23.1% discontinued treatment, respectively. The main reasons for switching anti-TNF agents in the first course were lack or loss of efficacy (LOE) and adverse events (AEs) in 40% and 30% of switchers, respectively. Similarly, reasons for switching during the second anti-TNF course were LOE in 48% and AEs in 28% of switchers. Of the 467 SpA patients starting anti-TNF therapy, 28% switched to a second and 8% switched to a third therapy. Mean drug survival for the first, second and third anti-TNF courses were 84.4 (95% CI 78.4, 90.5), 70.2 (95% CI 61.6, 78.9) and 64.8 (95% CI 51.1, 78.5) months, respectively (P = 0.315). CONCLUSION Twenty-eight per cent of SpA patients starting anti-TNF therapy switched to a second anti-TNF agent. Drug survival did not differ among anti-TNF courses. The main reason for switching anti-TNF therapy was LOE. Switchers were more frequently women and had higher disease activity parameters at the time of the study than non-switchers.

To assess white matter (WM) and gray matter (GM) magnetization transfer ratio histogram peak heights (MTR-HPHs) in different subsets of patients with neuropsychiatric systemic lupus erythematosus (NPSLE) who have unremarkable findings on 3T magnetic resonance imaging of the brain and to evaluate whether these values could be used to highlight different clinically suspected underlying pathogenic processes or identify the clinical NPSLE status or whether they could be associated with a specific NPSLE syndrome.Sixty-four SLE patients with neuropsychiatric symptoms were included. The initial NPSLE diagnosis and suspected underlying pathogenic process were established by multidisciplinary evaluation. The final diagnosis was made after also considering the disease course 6-18 months later. Thirty-three patients with central nervous system (CNS) NPSLE and 31 SLE patients with neuropsychiatric symptoms unrelated to SLE (non-SLE-related NP) were included. Twenty SLE patients without neuropsychiatric symptoms and 36 healthy control subjects were included for comparison. Differences in the WM and GM mean MTR-HPHs and between the different NPSLE subgroups (CNS NPSLE diagnosis, NPSLE phenotype [inflammatory or ischemic], and clinical changes after treatment) and the relationship to NPSLE syndromes were evaluated.Patients with inflammatory NPSLE had significantly lower WM MTR-HPHs than did the healthy controls, the SLE patients, and the non-SLE-related NP patients. Cognitive disorder, mood disorder, and psychosis were related to lower WM MTR-HPH values and cerebrovascular symptoms to higher values. Furthermore, the mean MTR-HPHs in the WM increased when the clinical status of the NPSLE patients improved.Measurement of MTR-HPH of the WM has the potential to identify inflammatory NPSLE with CNS involvement. This finding underscores the usefulness of this technique for the detection of cerebral changes in NPSLE patients and for the assessment of clinical changes after treatment.

Objectives To perform fine mapping of the PXK locus associated with systemic lupus erythematosus (SLE) and study functional effects that lead to susceptibility to the disease. Methods Linkage disequilibrium (LD) mapping was conducted by using 1251 SNPs (single nucleotide polymorphism) covering a 862 kb genomic region on 3p14.3 comprising the PXK locus in 1467 SLE patients and 2377 controls of European origin. Tag SNPs and genotypes imputed with IMPUTE2 were tested for association by using SNPTEST and PLINK. The expression QTLs data included three independent datasets for lymphoblastoid cells of European donors: HapMap3, MuTHER and the cross-platform eQTL catalogue. Correlation analysis of eQTLs was performed using Vassarstats. Alternative splicing for the PXK gene was analysed on mRNA from PBMCs. Results Fine mapping revealed long-range LD (>200 kb) extended over the ABHD6, RPP14, PXK, and PDHB genes on 3p14.3. The highly correlated variants tagged an SLE-associated haplotype that was less frequent in the patients compared with the controls (OR=0.89, p=0.00684). A robust correlation between the association with SLE and enhanced expression of ABHD6 gene was revealed, while neither expression, nor splicing alterations associated with SLE susceptibility were detected for PXK. The SNP allele frequencies as well as eQTL pattern analysed in the CEU and CHB HapMap3 populations indicate that the SLE association and the effect on ABHD6 expression are specific to Europeans. Conclusions These results confirm the genetic association of the locus 3p14.3 with SLE in Europeans and point to the ABHD6 and not PXK, as the major susceptibility gene in the region. We suggest a pathogenic mechanism mediated by the upregulation of ABHD6 in individuals carrying the SLE-risk variants.

Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage., Graphical abstract, Highlights • NAWM is investigated in NPSLE and SLE using MTI and DTI. • Differences in DTI and MTR between NPSLE and HC are widespread but only moderately co-localized. • Significant differences in MD between SLE and NPSLE suggest link to onset of NPSLE.

Journal Article; Vitamin D deficiency is associated with higher cardiovascular risk and metabolic syndrome (MeS) criteria. The main objective of this study was to analyse the association of 25-hydroxyvitamin D (25-OHD) serum levels with MeS (National Cholesterol Education Program-Adult Treatment Panel-III criteria) in 46 Spanish patients with psoriasis, but without arthritis and systemic treatment, and 46 control subjects, matched by sex and age. The patients with psoriasis showed significantly lower level of 25-OHD than controls (30.5 vs. 38.3 ng/ml; p = 0.0001). Patients with MeS had significantly lower serum levels of 25-OHD than those without MeS (24.1 ± 7.5 vs. 32.8 ± 8.9, p = 0.007), and a negative correlation was found between 25-OHD and waist circumference, diastolic blood pressure, fasting glucose, and triglyceridaemia. In the control group no significant correlation between 25-OHD and MeS was found. Al-though the sample was small, our results suggest a potential protective role for 25-OHD in the metabolic profile of patients with psoriasis without arthritis. Yes

Objective To assess cardiovascular (CV) risk in psoriatic arthritis (PsA) patients without clinically evident CV disease or classic atherosclerosis risk factors according to the SCORE chart following the EULAR recommendations. Methods Eighty PsA patients without previous CV events or atherosclerosis risk factors and eighty matched controls were included. Information on demographic, anthropometric and clinical-serological data of disease was assessed. The national calibrated Systematic Coronary Risk Evaluation (SCORE) index was calculated and the association between this SCORE and clinical-serological data of these patients was analyzed. Results PsA patients had higher acute phase reactants as well as higher SCORE mean values than healthy controls (1.99 ± 3.52 vs. 1.0 ± 1.74; P = 0.028). According to SCORE definitions, 71 (89%) patients had low-intermediate CV risk and 9 (11%) were above the threshold of high risk. In the control group, 76 (95%) had low-intermediate risk and four (5%) had high CV risk. However, there were no differences in CV risk stratification between both groups ( P = 0.148). PsA patients with high-very high CV risk had longer disease duration ( P = 0.001) and higher levels of triglycerides ( P = 0.009). PsA patients showed a significant correlation between SCORE values and disease duration (β = 0.185; P = 0.0001) and the average annual levels of C reactive protein (CRPa), β = 2.38; P = 0.014. Conclusion CV risk assessment in PsA patients without clinically evident CV disease or classic atherosclerosis risk factors may be underestimated by using only the SCORE chart. In these patients, disease duration and the CRPa may help to establish a better stratification of the actual CV risk.

Eosinophilic fasciitis is suspected in a patient with eosinophilia and characteristic cutaneous features.

Cluster Analysis of an Array of Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus

Background Psoriasis has been related to a higher prevalence of cardiovascular risk factors. Vitamin-D deficiency has been associated with metabolic syndrome, cardiovascular disease, and psoriasis. However, there has been no comparative study on the effects of vitamin-D status between patients with and without psoriatic arthritis. Objective The objective was to assess the relationship of 25-hydroxyvitamin D [25-(OH)D] levels with lipid and glucose metabolism parameters in psoriatic patients with and without arthritis. Methods We studied 122 patients with psoriasis (61 without arthritis and 61 with arthritis) from the psoriasis unit (dermatology department) and rheumatology department of our hospital, analyzing lipid and glucose metabolism variables and serum 25-(OH)D concentrations. Measurements were conducted within a 2-month period to minimize seasonal bias in 25-(OH)D levels. Results In the psoriatic patients without arthritis, serum 25-(OH)D levels were inversely correlated with fasting glucose ( r = −0.285; P = .026), total cholesterol ( r = −0.440; P = .000), low-density lipoprotein ( r = −0.415; P = .001), total cholesterol/high-density lipoprotein ( r = −0.303; P = .01), and triglyceride ( r = −0.280; P = .029) values. This association remained statistically significant for glucose, total cholesterol, and low-density lipoprotein after controlling for confounding factors in multivariate analysis. No association was found between serum 25-(OH)D levels and any metabolic parameter in the patients with psoriatic arthritis. Limitations This is a cross-sectional study that supports the hypothesis of an association between vitamin D and metabolic parameters but does not establish a causal relationship. Conclusions Serum 25-(OH)D was inversely related to lipid and glucose metabolism parameters in psoriatic patients without arthritis, whereas no such association was observed in psoriatic patients with arthritis. Interventional studies are warranted to assess the effects of vitamin-D supplements on the metabolic profile of psoriatic patients without arthritis.

Among the 12 systemic lupus erythematosus (SLE)-related central nervous system (CNS) syndromes defined by the American College of Rheumatology (ACR), demyelinating syndrome and myelopathy are two of the less prevalent and more poorly understood ones. One important issue concerning demyelinating disease in SLE is that it can be easily misdiagnosed with other central nervous system demyelinating disorders such as multiple sclerosis (MS). A clinically isolated neurological syndrome can be the presenting feature before other concomitant symptoms of SLE appear or definite MS is diagnosed. Although challenging, some diagnostic tests used in clinical practice and research may help to differentiate between these entities. These tests have improved the understanding of the pathogenesis in these diseases, but some points, such as the role of antiphospholipid antibodies in SLE-associated transverse myelitis, remain unclear and are a matter of ongoing debate. This review discusses clinical, pathophysiological, radiological and therapeutic concepts of demyelinating disease of the CNS in SLE, focussing on its differentiation from MS and its relation with other CNS demyelinating processes, such as transverse myelitis, optic neuritis and neuromyelitis optica.

Background Experimental SLE-models show that complement activation may be a key part of lupus cerebritis and lupus-thrombosis. It is also known that complement factors contribute to the pathology of inflammatory central nervous system (CNS) and neurodegenerative diseases Objectives To analyse serum levels of anti-C1q, C1q circulating immune complexes (CIC), complement activation and complement components in systemic lupus erythematosus (SLE) patients during the first CNS neuropsychiatric (NP) event and to define the possible association between these results and clinical and laboratory characteristics Methods Patients suspected of having NP involvement due to SLE were recruited in the Leiden NPSLE-clinic. All SLE patients were classified according to the ACR 1982 revised criteria for the classification of SLE. The clinical disease activity was measured by the SLE Disease Activity Index 2000 (SLEDAI-2K) and NP diagnoses were classified according to the 1999 ACR case definitions for NPSLE. We measured in serum of all patients anti-C1q and C1q CIC levels using ELISA, the activation capacity of complement (CH50 and AP50) using functional assays and different complement components (C1q, C3, C4) using laser nephelometry. Two-hundred healthy controls (HC) were also included for comparison Results A total of 280 patients were included. In 92 patients the symptoms were attributed to SLE. NPSLE patients consisted of 63 patients with focal NPSLE and 34 patients with diffuse NPSLE. Anti-C1q antibodies were significantly higher and CH50, AP50 and C3 were significantly lower in NPSLE patients compared to SLE and HC. This association was specially marked for diffuse NPSLE (SLE: 20.8 versus 8.7; HC: 20,8 versus 7,04; both comparisons P P P P P P P P P P Conclusions No association was found between anti-C1q, C1q CIC and NPSLE. The associations between diffuse NPSLE and low C3/AP50 and focal NPSLE and low C4 may be explained by disease activity and the presence of aPL respectively. The role of complement activation and complement components in lupus psychosis and cognitive dysfunction merits further research References Jacob A et al. C3aR inhibition reduces neurodegeneration in experimental lupus. Lupus 2010;19:73–82 Disclosure of Interest None declared

Joint Bone Spine - In Press.Proof corrected by the author Available online since samedi 30 juin 2012

Cellulosimicrobium cellulans has been reported as a rare cause of human pathogenesis. Infections mainly occur in immunocompromised patients and very often are associated with a foreign body. We report the first case of septic arthritis caused by C. cellulans in an immunocompetent patient. Our patient suffered a penetrating palm tree thorn injury to his left knee 8 weeks before admission. Although no foreign objects were found, they were suspected because previous reports suggest a frequent association with this microorganism, and open debridament was performed. Removal of foreign bodies related to this organism must be considered a high-priority treatment in these patients to achieve a complete recovery.

AA (secondary) amyloidosis is one of the most severe and uncommon complications of several rheumatic disorders and chronic infections such as tuberculosis (TB). Successful treatment depends on the control of the underlying inflammatory process, what can lead to an improvement or a regression in organ dysfunction. If the disorder persists, it has been reported in some cases of AA amyloidosis secondary to rheumatic diseases, that the use of biologic therapy is so far the only opportunity to reduce the development of AA amyloidosis and to reverse established deposits. We report herein a case of a latent TB infection complicated by a life-threatening AA amyloidosis presented as nephrotic syndrome. After an adequate antituberculostatic treatment, AA amyloidosis remained active and Tocilizumab (TCZ) was started with a dramatic resolution of the proteinuria, stabilization of the amyloid deposits and improvement in general condition.