Quantitative susceptibility mapping in the thalamus and basal ganglia of systemic lupus erythematosus patients with neuropsychiatric complaints.

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.

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

Anti-Inflammatory and Proresolving Effects of the Omega-6 Polyunsaturated Fatty Acid Adrenic Acid.

Polyunsaturated fatty acids (PUFAs) and their metabolites are potent regulators of inflammation. Generally, omega (n)-3 PUFAs are considered proresolving whereas n-6 PUFAs are classified as proinflammatory. In this study, we characterized the inflammatory response in murine peritonitis and unexpectedly found the accumulation of adrenic acid (AdA), a poorly studied n-6 PUFA. Functional studies revealed that AdA potently inhibited the formation of the chemoattractant leukotriene B4 (LTB4), specifically in human neutrophils, and this correlated with a reduction of its precursor arachidonic acid (AA) in free form. AdA exposure in human monocyte-derived macrophages enhanced efferocytosis of apoptotic human neutrophils. In vivo, AdA treatment significantly alleviated arthritis in an LTB4-dependent murine arthritis model. Our findings are, to our knowledge, the first to indicate that the n-6 fatty acid AdA effectively blocks production of LTB4 by neutrophils and could play a role in resolution of inflammation in vivo.

Ten years of METEOR (an international rheumatoid arthritis registry): development, research opportunities and future perspectives.

OBJECTIVES: Ten years ago, the METEOR tool was developed to simulate treatment-to-target and create an international research database. The development of the METEOR tool and database, research opportunities and future perspectives are described. METHODS: The METEOR tool is a free, online, internationally available tool in which daily practice visits of all rheumatoid arthritis patients visiting a rheumatologist can be registered. In the tool, disease characteristics, patient- and physician-reported outcomes and prescribed treatment could be entered. These can be subsequently displayed in powerful graphics, facilitating treatment decisions and patient-physician interactions. An upload facility is also available, by which data from local electronic health record systems or registries can be integrated into the METEOR database. This is currently being actively used in, among other countries, the Netherlands, Portugal and India. RESULTS: Since an increasing number of hospitals use electronic health record systems, the upload facility is being actively used by an increasing number of sites, enabling them to benefit from the benchmark and research opportunities of METEOR. Enabling a connection between local registries and METEOR is a well established but time-consuming process for which an IT-specialist of METEOR and the local registry are necessary. However, once this process has been finished, data can be uploaded regularly and relatively easily according to a pre-specified format. The METEOR database currently contains data from >39,000 patients and >200,000 visits, from 32 different countries and is ever increasing. Continuous efforts are being undertaken to increase the quality of data in the database. CONCLUSIONS: Since METEOR was founded 10 years ago, many rheumatologists worldwide have used the METEOR tool to follow-up their patients and improve the quality of care they provide to their patients. Combined with uploaded data, this has led to an extensive growth of the database. It now offers a unique opportunity to study daily practice care and to perform research regarding cross-country differences in a large, worldwide setting, which could provide important knowledge about disease and its treatment in different geographic and clinical settings.

Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis.

OBJECTIVE: To determine whether anticitrullinated protein antibodies (ACPA) exhibit specific changes in Fc glycosylation prior to the onset of arthritis. METHODS: Serum samples of patients with ACPA-positive arthralgia (n=183) were collected at baseline and at various time points of follow-up. 105 patients developed arthritis after a median of 12 months (IQR 6-24) and were classified as having either rheumatoid arthritis (RA, n=48) or undifferentiated arthritis (UA, n=57) based on the 1987 American College of Rheumatology (ACR) criteria. ACPA and total serum IgG were isolated by affinity purification and cleaved by trypsin. ACPA-IgG1 Fc-glycopeptides were subsequently analysed by nano-liquid chromatography mass spectrometry and compared to those of total IgG1. RESULTS: At baseline, ACPA-IgG1 and total IgG1 from arthralgia patients displayed similar Fc glycosylation patterns. By contrast, at the onset of arthritis, ACPA exhibited a decrease in galactose residues in RA patients, but not in UA patients. This decrease occurred around 3 months prior to diagnosis and was paralleled by an increase in systemic inflammation (erythrocyte sedimentation rate). Galactosylation of total IgG1 was also decreased in RA, but this did not precede the onset of arthritis. Interestingly, we additionally noted a higher degree of ACPA-IgG1 Fc core fucosylation at baseline as compared with total IgG1, which further increased prior to diagnosis. CONCLUSIONS: ACPA display significant changes in Fc galactosylation and fucosylation prior to the onset of RA. These changes towards a more pro-inflammatory phenotype could be involved in driving the disease process.

Personalized medicine: predicting responses to therapy in patients with RA.

Personalized medicine where each patient receives the right drug and the right intensity of drug treatment for as long as needed or safe is the goal of medicine. The identification of predictors of response is the first step toward this. In rheumatoid arthritis (RA), several prediction matrices were designed to predict the risk of rapid radiological progression (RRP) in the first year of treatment, on either disease modifying anti-rheumatic drug (DMARD) monotherapy or combination therapy with prednisone or a biological agent. Both clinical markers and biomarkers of response to either anti-TNF or different mode of action biological agents, and of successful discontinuation of these agents once the treatment goal has been achieved, have been identified in different studies. Most of these markers need validation in other cohorts. Research into combining clinical markers and biomarkers of response could lead to identification of risk profiles resulting in a new step toward personalized medicine in RA.

An innovative care model coordinated by a physical therapist and nurse practitioner for osteoarthritis of the hip and knee in specialist care: a prospective study.

The subject of the study is to investigate whether health-related quality of life (HRQoL), pain and function of patients with hip or knee osteoarthritis (OA) improves after a specialist care intervention coordinated by a physical therapist and a nurse practitioner (NP) and to assess satisfaction with this care at 12 weeks. This observational study included all consecutive patients with hip or knee OA referred to an outpatient orthopaedics clinic. The intervention consisted of a single, standardized visit (assessment and individually tailored management advice, to be executed in primary care) and a telephone follow-up, coordinated by a physical therapist and a NP, in cooperation with an orthopaedic surgeon. Assessments at baseline and 10 weeks thereafter included the short form-36 (SF-36), EuroQol 5D (EQ-5D), hip or knee disability and osteoarthritis outcome score (HOOS or KOOS), the intermittent and constant osteoarthritis pain questionnaire (ICOAP) for hip or knee and a multidimensional satisfaction questionnaire (23 items; 4 point scale). Eighty-seven patients (57 female), mean age 68 years (SD 10.9) were included, with follow-up data available in 63 patients (72 %). Statistically significant improvements were seen regarding the SF-36 physical summary component score, the EQ-5D, the ICOAP scores for hip and knee, the HOOS subscale sports and the KOOS subscales pain, symptoms and activities of daily living. The proportions of patients reporting to be satisfied ranged from 79 to 98 % per item. In patients with hip and knee OA pain, function and HRQoL improved significantly after a single-visit multidisciplinary OA management intervention in specialist care, with high patient satisfaction.

Rheumatoid arthritis.

Rheumatoid arthritis is characterised by persistent synovitis, systemic inflammation, and autoantibodies (particularly to rheumatoid factor and citrullinated peptide). 50% of the risk for development of rheumatoid arthritis is attributable to genetic factors. Smoking is the main environmental risk. In industrialised countries, rheumatoid arthritis affects 0·5-1·0% of adults, with 5-50 per 100 000 new cases annually. The disorder is most typical in women and elderly people. Uncontrolled active rheumatoid arthritis causes joint damage, disability, decreased quality of life, and cardiovascular and other comorbidities. Disease-modifying antirheumatic drugs (DMARDs), the key therapeutic agents, reduce synovitis and systemic inflammation and improve function. The leading DMARD is methotrexate, which can be combined with other drugs of this type. Biological agents are used when arthritis is uncontrolled or toxic effects arise with DMARDs. Tumour necrosis factor inhibitors were the first biological agents, followed by abatacept, rituximab, and tocilizumab. Infections and high costs restrict prescription of biological agents. Long-term remission induced by intensive, short-term treatment selected by biomarker profiles is the ultimate goal.

Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis.

Wyeth Research was developing apratastat (TMI-005), one in a series of dual TNFalpha-converting enzyme and matrix metalloprotease-13 inhibitors, for the potential treatment of inflammation, especially rheumatoid arthritis. By January 2005, apratastat had entered a phase II clinical trial; however, in October 2006, Wyeth reported that it had terminated development of the drug because of lack of efficacy in this trial.